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1.  Chaperones in autophagy 
Cells continuously turn over proteins through cycles of synthesis and degradation in order to maintain a functional proteome and to exert a tight control in the levels of regulatory proteins. Selective degradation of proteins was initially thought to be an exclusive function of the ubiquitin-proteasome system however, over the years, the contribution of lysosomes to this selective degradation, through the process of autophagy, has become consolidated. In this context, molecular chaperones, classically associated with protein folding, unfolding and assembling, have been revealed as important modulators of selectivity during the autophagic process. Here, we review this relatively new role of chaperones in mediating selective autophagy and comment on how alterations of this function can lead to human pathologies associated to proteotoxicity.
PMCID: PMC3502706  PMID: 23059540
Aging; chaperones; lysosomes; membrane proteins; protein degradation
2.  Dietary lipids and aging compromise chaperone-mediated autophagy by similar mechanisms 
Autophagy  2012;8(7):1152-1154.
Chaperone-mediated autophagy (CMA) is a selective form of autophagy whose distinctive feature is the fact that substrate proteins are translocated directly from the cytosol across the lysosomal membrane for degradation inside lysosomes. CMA substrates are cytosolic proteins bearing a pentapeptide motif in their sequence that, when recognized by the cytosolic chaperone HSPA8/HSC70, targets them to the surface of the lysosomes. Once there, substrate proteins bind to the lysosome-associated membrane protein type 2 isoform A (LAMP2A), inducing assembly of this receptor protein into a higher molecular weight protein complex that is used by the substrate proteins to reach the lysosomal lumen. CMA is constitutively active in most cells but it is maximally activated under conditions of stress.
PMCID: PMC3429556  PMID: 22653298
cholesterol; diet; lipid microdomains; lipidomic analysis; lysosomes; membrane proteins; proteolysis
3.  Protein Homeostasis and Aging: the importance of exquisite quality control 
Ageing research reviews  2010;10(2):205-215.
All cells count on precise mechanisms that regulate protein homeostasis to maintain a stable and functional proteome. A progressive deterioration in the ability of cells to preserve the stability of their proteome occurs with age and contributes to the functional loss characteristic of old organisms. Molecular chaperones and the proteolytic systems are responsible for this cellular quality control by assuring continuous renewal of intracellular proteins. When protein damage occurs, such as during cellular stress, the coordinated action of these cellular surveillance systems allows detection and repair of the damaged structures or, in many instances, leads to the complete elimination of the altered proteins from inside cells. Dysfunction of the quality control mechanisms and intracellular accumulation of abnormal proteins in the form of protein inclusions and aggregates occur in almost all tissues of an aged organism. Preservation or enhancement of the activity of these surveillance systems until late in life improves their resistance to stress and is sufficient to slow down aging. In this work, we review recent advances on our understanding of the contribution of chaperones and proteolytic systems to the maintenance of cellular homeostasis, the cellular response to stress and ultimately to longevity.
PMCID: PMC2888802  PMID: 20152936
Autophagy; chaperones; proteases; proteasome; proteolysis; ubiquitin
4.  Chaperone-mediated Autophagy in Protein Quality Control 
Current opinion in cell biology  2010;23(2):184-189.
Chaperone-mediated autophagy is a selective mechanism for degradation of soluble cytosolic proteins in lysosomes that distinguishes itself from other autophagic pathways by the selectivity with which CMA substrates are targeted for degradation. The recent molecular dissection of this autophagic pathway and the development of experimental models with compromised CMA have unveiled the important contribution of this pathway to protein quality control. In fact, CMA activation seems to be a common mechanism of cellular defense against proteotoxicity.
PMCID: PMC3078170  PMID: 21094035
chaperones; lysosomes; oxidative stress; proteases; selective autophagy
5.  Chaperone-mediated autophagy: Molecular mechanisms and physiological relevance 
Chaperone-mediated autophagy (CMA) is a selective lysosomal pathway for the degradation of cytosolic proteins. We review in this work some of the recent findings on this pathway regarding the molecular mechanisms that contribute to substrate targeting, binding and translocation across the lysosomal membrane. We have placed particular emphasis on the critical role that changes in the lipid composition of the lysosomal membrane play in the regulation of CMA, as well as the modulatory effect of other novel CMA components. In the second part of this review, we describe the physiological relevance of CMA and its role as one of the cellular mechanisms involved in the response to stress. Changes with age in CMA activity and the contribution of failure of CMA to the phenotype of aging and to the pathogenesis of several age-related pathologies are also described.
PMCID: PMC2914824  PMID: 20176123
chaperones; lysosomes; membrane proteins; protein translocation; proteases; proteolysis
6.  Chaperone-Mediated Autophagy 
Continuous renewal of intracellular components is required to preserve cellular functionality. In fact, failure to timely turnover proteins and organelles leads often to cell death and disease. Different pathways contribute to the degradation of intracellular components in lysosomes or autophagy. In this review, we focus on chaperone-mediated autophagy (CMA), a selective form of autophagy that modulates the turnover of a specific pool of soluble cytosolic proteins. Selectivity in CMA is conferred by the presence of a targeting motif in the cytosolic substrates that, upon recognition by a cytosolic chaperone, determines delivery to the lysosomal surface. Substrate proteins undergo unfolding and translocation across the lysosomal membrane before reaching the lumen, where they are rapidly degraded. Better molecular characterization of the different components of this pathway in recent years, along with the development of transgenic models with modified CMA activity and the identification of CMA dysfunction in different severe human pathologies and in aging, are all behind the recent regained interest in this catabolic pathway.
PMCID: PMC3137147  PMID: 20160146
aging; lysosomes; membrane proteins; proteases; protein translocation
7.  Chaperone-mediated autophagy: a unique way to enter the lysosome world 
Trends in cell biology  2012;22(8):407-417.
All cellular proteins undergo continuous synthesis and degradation. This permanent renewal is necessary to maintain a functional proteome and to allow for rapid changes in levels of specific proteins with regulatory purposes. Although for a long time lysosomes were considered unable to contribute to the selective degradation of individual proteins, the discovery of chaperone-mediated autophagy (CMA) changed this notion. Here, we review the characteristics that set CMA apart from other types of lysosomal degradation and the subset of molecules that confer cells the capability to identify individual cytosolic proteins and direct them across the lysosomal membrane for degradation.
PMCID: PMC3408550  PMID: 22748206
aging; cancer; chaperones; lysosomes; membrane proteins; neurodegeneration; protein degradation
8.  Functional interaction between autophagy and ciliogenesis 
Nature  2013;502(7470):194-200.
Nutrient deprivation is a stimulus shared by both autophagy and the formation of primary cilia. The recently discovered role of primary cilia in nutrient sensing and signaling motivated us to explore the possible functional interactions between this signaling hub and autophagy. Here we show that part of the molecular machinery involved in ciliogenesis also participates in the early steps of the autophagic process. Signaling from the cilia, such as that from the Hedgehog pathway, induces autophagy by acting directly on essential autophagy-related proteins strategically located in the base of the cilium by ciliary trafficking proteins. While abrogation of ciliogenesis partially inhibits autophagy, blockage of autophagy enhances primary cilia growth and cilia-associated signaling during normal nutritional conditions. We propose that basal autophagy regulates ciliary growth through the degradation of proteins required for intraflagellar transport. Compromised ability to activate the autophagic response may underlie the basis of some common ciliopathies.
PMCID: PMC3896125  PMID: 24089209
primary cilia; intraflagellar transport proteins; lysosomes; autophagosomes; vesicular trafficking
9.  Integration of Clearance Mechanisms: The Proteasome and Autophagy 
Cells maintain a healthy proteome through continuous evaluation of the quality of each of their proteins. Quality control requires the coordinated action of chaperones and proteolytic systems. Chaperones identify abnormal or unstable conformations in proteins and often assist them to regain stability. However, if repair is not possible, the aberrant protein is eliminated from the cellular cytosol to prevent undesired interactions with other proteins or its organization into toxic multimeric complexes. Autophagy and the ubiquitin/proteasome system mediate the complete degradation of abnormal protein products. In this article, we describe each of these proteolytic systems and their contribution to cellular quality control. We also comment on the cellular consequences resulting from the dysfunction of these systems in common human protein conformational disorders and provide an overview on current therapeutic interventions based on the modulation of the proteolytic systems.
Lysosomes and proteasomes are coordinated quality-control mechanisms that degrade abnormal proteins. In each case, the targets must be selected and tagged appropriately, and malfunctions can cause severe protein-conformation disorders.
PMCID: PMC2982176  PMID: 21068151
10.  Chaperone-mediated autophagy dysfunction in the pathogenesis of neurodegeneration 
Neurobiology of disease  2010;43(1):29-37.
Chaperone-mediated autophagy (CMA) contributes to selective degradation of individual soluble proteins in lysosomes. Unique to this type of autophagy is the fact that proteins reach the lysosomal lumen for degradation by directly crossing the lysosomal membrane, in contrast with the vesicle-mediated delivery characteristic of the other types of autophagy. These two characteristics - selective targeting and direct translocation of substrates - determine the contribution of CMA to different physiological functions and the type of pathological conditions associated with CMA dysfunction. In this review, we briefly revise recent findings on the molecular mechanisms behind CMA function, and describe the physiological relevance of the selective lysosomal degradation through this pathway. We also comment on the cellular consequences of CMA malfunction and on the connections already established between CMA dysfunction and different human disorders, with special emphasis on neurodegenerative diseases.
PMCID: PMC2998583  PMID: 20643207
aging; chaperones; lysosomes; neurodegeneration; Parkinson’s disease; proteases; proteotoxicity
11.  Constitutive upregulation of chaperone-mediated autophagy in Huntington’s disease 
The Journal of Neuroscience  2011;31(50):18492-18505.
Autophagy contributes to the removal of prone-to-aggregate proteins, but in several instances these pathogenic proteins have been shown to interfere with autophagic activity. In the case of Huntington’s disease (HD), a congenital neurodegenerative disorder resulting from mutation in the huntingtin protein, we have previously described that the mutant protein interferes with the ability of autophagic vacuoles to recognize cytosolic cargo. Growing evidence supports the existence of cross-talk among autophagic pathways, suggesting the possibility of functional compensation when one of them is compromised. In this study, we have identified a compensatory upregulation of chaperone-mediated autophagy (CMA) in different cellular and mouse models of HD. Components of CMA, namely the lysosome-associated membrane protein type 2A (LAMP-2A) and lysosomal-hsc70, are markedly increased in HD models. The increase in LAMP-2A is achieved through both an increase in the stability of this protein at the lysosomal membrane and transcriptional upregulation of this splice variant of the lamp-2 gene. We propose that CMA activity increases in response to macroautophagic dysfunction in the early stages of HD, but that the efficiency of this compensatory mechanism may decrease with age and so contribute to cellular failure and the onset of pathological manifestations.
PMCID: PMC3282924  PMID: 22171050
chaperones; lysosomal membrane proteins; lysosomes; neurodegeneration; proteotoxicity; proteolysis
Molecular cell  2010;39(4):535-547.
Chaperone-mediated autophagy (CMA) is a selective mechanism for the degradation of cytosolic proteins in lysosomes that contributes to cellular quality control and becomes an additional source of amino acids when nutrients are scarce. A chaperone complex delivers CMA substrates to a receptor protein at the lysosomal membrane that assembles into multimeric translocation complexes. However, the mechanisms regulating this process remain, for the most part, unknown. In this work, we have identified two regulatory proteins, GFAP and EF1α, that mediate a previously unknown inhibitory effect of GTP on CMA. GFAP stabilizes the multimeric translocation complex against chaperone-mediated disassembly, whereas GTP-mediated release of EF1α from the lysosomal membrane promotes self-association of GFAP, disassembly of the CMA translocation complex and the consequent decrease in CMA. The dynamic interactions of these two proteins at the lysosomal membrane unveil now a role for GTP as negative regulator of CMA.
PMCID: PMC2945256  PMID: 20797626
13.  Chaperone-mediated Autophagy in Health and Disease 
FEBS letters  2009;584(7):1399-1404.
Chaperone-mediated autophagy (CMA) is a lysosomal pathway that participates in the degradation of cytosolic proteins. CMA is activated by starvation and in response to stressors that result in protein damage. The selectivity intrinsic to CMA allows for removal of damaged proteins without disturbing nearby functional ones. CMA works in a coordinated manner with other autophagic pathways, which can compensate for each other. Interest in CMA has recently grown because of the connections established between this autophagic pathway and human pathologies. Here we review the unique properties of CMA compared to other autophagic pathways and its relevance in health and disease.
PMCID: PMC2843772  PMID: 20026330
aging; chaperones; cellular stress; lysosomes; proteases; protein translocation
14.  Entering the lysosome through a transient gate by chaperone-mediated autophagy 
Autophagy  2008;4(8):1101-1103.
A subset of cytosolic proteins can be selectively degraded in lysosomes through chaperone-mediated autophagy. The lysosomal-membrane protein type 2A (LAMP-2A) acts as the receptor for the substrates of chaperone-mediated autophagy (CMA), which should undergo unfolding before crossing the lysosomal membrane and reaching the lumen for degradation. Translocation of substrates is assisted by chaperones on both sides of the membrane, but the actual steps involved in this process and the characteristics of the translocation complex were, for the most part, unknown. We have now found that rather than a stable translocon at the lysosomal membrane, CMA substrates bind to monomers of LAMP-2A driving the organization of this protein into a high molecular weight multimeric complex that mediates translocation. Assembly and disassembly of LAMP-2A into and from this complex is dynamic and it is regulated by hsc70 and hsp90, the two lysosomal chaperones related to CMA. This work thus unveils a unique mechanism of protein translocation across the lysosomal membrane, which involves only transient discontinuity of the membrane. The possible advantages of this transitory lysosomal translocon are discussed in light of the unique properties of the lysosomal compartment.
PMCID: PMC2832301  PMID: 18927485
autophagy; chaperones; membrane dynamics; membrane proteins; protein translocation
15.  Chemical modulation of chaperone-mediated autophagy by retinoic acid derivatives 
Nature chemical biology  2013;9(6):374-382.
Chaperone-mediated autophagy (CMA) contributes to cellular quality control and the cellular response to stress through the selective degradation of cytosolic proteins in lysosomes. Decrease in CMA activity occurs in aging and in age-related disorders (for example, neurodegenerative diseases and diabetes). Although prevention of this age-dependent decline through genetic manipulation in mouse has proven beneficial, chemical modulation of CMA is not currently possible, due in part to the lack of information on the signaling mechanisms that modulate this pathway. In this work, we report that signaling through the retinoic acid receptor alpha (RARα) inhibits CMA and apply structure-based chemical design to develop synthetic derivatives of all-trans-retinoic acid (ATRA) to specifically neutralize this inhibitory effect. We demonstrate that chemical enhancement of CMA protects cells from oxidative stress and from proteotoxicity, supporting a potential therapeutic opportunity when reduced CMA contributes to cellular dysfunction and disease.
PMCID: PMC3661710  PMID: 23584676
all-trans-retinoic acid; lysosomes; oxidative stress; proteotoxicity; retinoic acid receptor
16.  Constitutive Activation of Chaperone-mediated Autophagy in Cells with Impaired Macroautophagy 
Molecular Biology of the Cell  2008;19(5):2179-2192.
Three different types of autophagy—macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA)—contribute to degradation of intracellular components in lysosomes in mammalian cells. Although some level of basal macroautophagy and CMA activities has been described in different cell types and tissues, these two pathways are maximally activated under stress conditions. Activation of these two pathways is often sequential, suggesting the existence of some level of cross-talk between both stress-related autophagic pathways. In this work, we analyze the consequences of blockage of macroautophagy on CMA activity. Using mouse embryonic fibroblasts deficient in Atg5, an autophagy-related protein required for autophagosome formation, we have found that blockage of macroautophagy leads to up-regulation of CMA, even under basal conditions. Interestingly, different mechanisms contribute to the observed changes in CMA-related proteins and the consequent activation of CMA during basal and stress conditions in these macroautophagy-deficient cells. This work supports a direct cross-talk between these two forms of autophagy, and it identifies changes in the lysosomal compartment that underlie the basis for the communication between both autophagic pathways.
PMCID: PMC2366850  PMID: 18337468
17.  Interplay of LRRK2 with chaperone-mediated autophagy 
Nature neuroscience  2013;16(4):394-406.
Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson’s disease (PD). In this work, we demonstrate that LRRK2 can be degraded in lysosomes by chaperone-mediated autophagy (CMA), whereas the most common pathogenic mutant form of LRRK2, G2019S, is poorly degraded by this pathway. In contrast to typical CMA substrates, lysosomal binding of both wild-type and several pathogenic mutant LRRK2 proteins is enhanced in the presence of other CMA substrates, which interferes with the organization of the CMA translocation complex, resulting in defective CMA. Cells respond to such LRRK2-mediated CMA compromise by increasing levels of the CMA lysosomal receptor as seen in neuronal cultures and brains of LRRK2 transgenic mice, iPSC-derived dopaminergic neurons, and brains of mutant LRRK2 PD patients. This novel LRRK2 self-perpetuating inhibitory effect on CMA could underlie toxicity in PD by compromising the degradation of alpha-synuclein, another PD-related protein degraded by this pathway.
PMCID: PMC3609872  PMID: 23455607
chaperones; lysosomal membrane proteins; lysosomes; neurodegeneration; Parkinson’s disease; proteotoxicity; induced pluripotent stem cells
Nature communications  2012;3:1240.
Protein quality control is essential for cellular survival. Failure to eliminate pathogenic proteins leads to their intracellular accumulation in the form of protein aggregates. Autophagy can recognize protein aggregates and degrade them in lysosomes. However, some aggregates escape the autophagic surveillance. Here we analyze the autophagic degradation of different types of aggregates of synphilin-1 (Sph1), a protein often found in pathogenic protein inclusions. We show that small Sph1 aggregates and large aggresomes are differentially targeted by constitutive and inducible autophagy. Furthermore, we identify a region in Sph1 necessary for its own basal and inducible aggrephagy, and sufficient for the degradation of other pro-aggregating proteins. Although the presence of this peptide is sufficient for basal aggrephagy, inducible aggrephagy requires its ubiquitination, which diminishes protein mobility on the surface of the aggregate and favors the recruitment and assembly of the protein complexes required for autophagosome formation. Our study reveals different mechanisms for cells to cope with aggregate proteins via autophagy and supports the idea that autophagic susceptibility of prone-to-aggregate proteins may not depend on the nature of the aggregating proteins per se but on their dynamic properties in the aggregate.
PMCID: PMC3526956  PMID: 23212369
autophagy; protein aggregates; aggresomes; synphilin-1; protein mobility; ubiquitination
19.  Targeting the UPR transcription factor XBP1 protects against Huntington's disease through the regulation of FoxO1 and autophagy 
Human Molecular Genetics  2012;21(10):2245-2262.
Mutations leading to expansion of a poly-glutamine track in Huntingtin (Htt) cause Huntington's disease (HD). Signs of endoplasmic reticulum (ER) stress have been recently reported in animal models of HD, associated with the activation of the unfolded protein response (UPR). Here we have investigated the functional contribution of ER stress to HD by targeting the expression of two main UPR transcription factors, XBP1 and ATF4 (activating transcription factor 4), in full-length mutant Huntingtin (mHtt) transgenic mice. XBP1-deficient mice were more resistant to developing disease features, associated with improved neuronal survival and motor performance, and a drastic decrease in mHtt levels. The protective effects of XBP1 deficiency were associated with enhanced macroautophagy in both cellular and animal models of HD. In contrast, ATF4 deficiency did not alter mHtt levels. Although, XBP1 mRNA splicing was observed in the striatum of HD transgenic brains, no changes in the levels of classical ER stress markers were detected in symptomatic animals. At the mechanistic level, we observed that XBP1 deficiency led to augmented expression of Forkhead box O1 (FoxO1), a key transcription factor regulating autophagy in neurons. In agreement with this finding, ectopic expression of FoxO1 enhanced autophagy and mHtt clearance in vitro. Our results provide strong evidence supporting an involvement of XBP1 in HD pathogenesis probably due to an ER stress-independent mechanism involving the control of FoxO1 and autophagy levels.
PMCID: PMC3335312  PMID: 22337954
20.  A comprehensive glossary of autophagy-related molecules and processes 
Autophagy  2010;6(4):438-448.
Autophagy is a rapidly expanding field in the sense that our knowledge about the molecular mechanism and its connections to a wide range of physiological processes has increased substantially in the past decade. Similarly, the vocabulary associated with autophagy has grown concomitantly. This fact makes it difficult for readers, even those who work in the field, to keep up with the ever-expanding terminology associated with the various autophagy-related processes. Accordingly, we have developed a comprehensive glossary of autophagy-related terms that is meant to provide a quick reference for researchers who need a brief reminder of the regulatory effects of transcription factors or chemical agents that induce or inhibit autophagy, the function of the autophagy-related proteins, or the role of accessory machinery or structures that are associated with autophagy.
PMCID: PMC3652604  PMID: 20484971
autophagy; definitions; glossary; lexicon; terms
21.  A photoconvertible fluorescent reporter to track chaperone-mediated autophagy 
Nature communications  2011;2:386.
Chaperone-mediated autophagy (CMA) is a selective mechanism for the degradation of soluble proteins in lysosomes. CMA contributes to cellular quality control and is activated as part of the cellular response to different stressors. Defective CMA has been identified in aging and different age-related diseases. Until now, CMA activity could only be measured in vitro upon isolation of lysosomes. Here we report the development of a photoconvertible fluorescent reporter that allows monitoring of CMA activity in living cells. Activation of CMA increases the association of the reporter with lysosomes which are visualized as a change in the intracellular fluorescence. The CMA reporter can be utilized in a broad variety of cells and is suitable for high-content microscopy. Using this reporter, we find that levels of basal and inducible CMA activity are cell-type dependent and we have identified an upregulation of this pathway in response to the catalytic inhibition of the proteasome.
PMCID: PMC3529934  PMID: 21750540
22.  A comprehensive glossary of autophagy-related molecules and processes (2nd edition) 
Autophagy  2011;7(11):1273-1294.
The study of autophagy is rapidly expanding, and our knowledge of the molecular mechanism and its connections to a wide range of physiological processes has increased substantially in the past decade. The vocabulary associated with autophagy has grown concomitantly. In fact, it is difficult for readers—even those who work in the field—to keep up with the ever-expanding terminology associated with the various autophagy-related processes. Accordingly, we have developed a comprehensive glossary of autophagy-related terms that is meant to provide a quick reference for researchers who need a brief reminder of the regulatory effects of transcription factors and chemical agents that induce or inhibit autophagy, the function of the autophagy-related proteins, and the roles of accessory components and structures that are associated with autophagy.
PMCID: PMC3359482  PMID: 21997368
autophagy; lysosome; mitophagy; pexophagy; stress; vacuole
23.  Autophagy modulates dynamics of connexins at the plasma membrane in a ubiquitin-dependent manner 
Molecular Biology of the Cell  2012;23(11):2156-2169.
Connexins modulate intercellular communication when assembled in gap junctions. Compromised macroautophagy increases cellular communication due to failure to degrade connexins at gap junctions. Nedd4-mediated ubiquitinylation of the connexin molecule is required to trigger its autophagy-dependent internalization and degradation.
Different pathways contribute to the turnover of connexins, the main structural components of gap junctions (GJs). The cellular pool of connexins targeted to each pathway and the functional consequences of degradation through these degradative pathways are unknown. In this work, we focused on the contribution of macroautophagy to connexin degradation. Using pharmacological and genetic blockage of macroautophagy both in vitro and in vivo, we found that the cellular pool targeted by this autophagic system is primarily the one organized into GJs. Interruption of connexins' macroautophagy resulted in their retention at the plasma membrane in the form of functional GJs and subsequent increased GJ-mediated intercellular diffusion. Up-regulation of macroautophagy alone is not sufficient to induce connexin internalization and degradation. To better understand what factors determine the autophagic degradation of GJ connexins, we analyzed the changes undergone by the fraction of plasma membrane connexin 43 targeted for macroautophagy and the sequence of events that trigger this process. We found that Nedd4-mediated ubiquitinylation of the connexin molecule is required to recruit the adaptor protein Eps15 to the GJ and to initiate the autophagy-dependent internalization and degradation of connexin 43. This study reveals a novel regulatory role for macroautophagy in GJ function that is directly dependent on the ubiquitinylation of plasma membrane connexins.
PMCID: PMC3364179  PMID: 22496425
24.  Autophagy in hypothalamic AgRP neurons regulates food intake and energy balance 
Cell metabolism  2011;14(2):173-183.
Macroautophagy is a lysosomal degradative pathway that maintains cellular homeostasis by turning over cellular components. Here, we demonstrate a role for autophagy in hypothalamic agouti-related peptide (AgRP) neurons in the regulation of food intake and energy balance. We show that starvation-induced hypothalamic autophagy mobilizes neuron-intrinsic lipids to generate endogenous free fatty acids, which in turn regulate AgRP levels. The functional consequences of inhibiting autophagy are the failure to upregulate AgRP in response to starvation, and constitutive increases in hypothalamic levels of pro-opiomelanocortin and its cleavage product α-melanocyte stimulating hormone that typically contribute to a lean phenotype. We propose a new conceptual framework for considering how autophagy-regulated lipid metabolism within hypothalamic neurons may modulate neuropeptide levels to have immediate effects on food intake, as well as long-term effects on energy homeostasis. Regulation of hypothalamic autophagy could become an effective intervention in conditions such as obesity and the metabolic syndrome.
PMCID: PMC3148494  PMID: 21803288
25.  Age-related Oxidative Stress Compromises Endosomal Proteostasis 
Cell reports  2012;2(1):136-149.
A hallmark of aging is an imbalance between production and clearance of reactive oxygen species and increased levels of oxidatively damaged biomolecules. Herein we demonstrate that splenic and nodal antigen presenting cells purified from old mice accumulate oxidatively modified proteins with side chain carbonylation, advanced glycation end products and lipid peroxidation. We show further that the endosomal accumulation of oxidatively modified proteins interferes with the efficient processing of exogenous antigens and degradation of macroautophagy-delivered proteins. In support of a causative role for oxidized products in the inefficient immune response, a decrease in oxidative stress improved the adaptive immune response to immunizing antigens. These findings underscore a previously unrecognized negative effect of age-dependent changes in cellular proteostasis on the immune response.
PMCID: PMC3408590  PMID: 22840404

Results 1-25 (50)