Autophagy is a conserved mechanism that is essential for cell survival in starvation. Moreover, autophagy maintains cellular health by clearing unneeded or harmful materials from cells. Autophagy proceeds by the engulfment of bulk cytosol and organelles by a cup-shaped double membrane sheet known as the phagophore. The phagophore closes upon itself to form the autophagosome, which delivers its contents to the vacuole or lysosome for degradation. A multiprotein complex consisting of the protein kinase Atg1 together with Atg13, Atg17, Atg29, and Atg31 (ULK1, ATG13, FIP200, and ATG101 in humans) has a pivotal role in the earliest steps of this process. This review summarizes recent structural and ultrastructural analysis of the earliest step in autophagosome biogenesis and discusses a model in which the Atg1 complex clusters high curvature vesicles containing the integral membrane protein Atg9, thereby initiating the phagophore.
SNAREs; Atg1; Atg9; Atg13; autophagy; ULK1; membrane bending; vesicle tethering
Eukaryotic cells compartmentalize their biochemical processes within organelles, which have specific functions that must be maintained for overall cellular health. As the site of aerobic energy mobilization and essential biosynthetic activities, mitochondria are critical for cell survival and proliferation. Here, we describe mechanisms to control the quality and quantity of mitochondria within cells with an emphasis on findings from the budding yeast, Saccharomyces cerevisiae. We also describe how mitochondrial quality and quantity control systems that operate during cell division affect lifespan and cell cycle progression.
mitochondria; inheritance; lifespan; cell division; yeast
Recently, several publications have surfaced describing methods to manipulate mitochondrial genomes in tissues and embryos. With them, a somewhat sensationalistic uproar about the generation of children with ‘three parents’ has dominated the discussion in the lay media. It is important that society understands the singularities of mitochondrial genetics to judge these procedures in a rational light, so that this ongoing discussion does not preclude the helping of patients and families harboring mutated mitochondrial genomes.
Transcriptional regulation is an essential component of tumor progression and metastasis. During cancer progression, dysregulation of oncogenic or tumor suppressive transcription factors, as well as master cell fate regulators and tumor microenvironment-induced factors, collectively influence multiple steps of the metastasis cascade, including local invasion, dissemination, and eventual colonization of the tumor to distant organs. Furthermore, epigenetic alterations in tumor cells, including DNA methylation, as well as activation or suppression of histone deacetylases (HDACs), histone acetyltransferases (HATs), and other chromatin modifying enzymes can further distort the transcriptional network to influence metastasis. We focus here on recent research advances in transcriptional control of metastasis and highlight the therapeutic potential of targeting such transcriptional regulatory networks.
transcription factors; metastasis; epithelial-mesenchymal transition; tumor microenvironment; epigenetics
Axons are specialized extensions of neurons that are critical for the organization of the nervous system. In order to maintain function in axons that often extend some distance from the cell body, specialized mechanisms of energy delivery are likely necessary. Over the last decade, greater understanding of human demyelinating diseases and the development of animal models have suggested that oligodendroglia are critical for maintaining the function of axons. In this review, we will discuss evidence for the vulnerability of neurons to energy deprivation, the importance of oligodendrocytes for axon function and survival, and very recent data suggesting that transfer of energy metabolites from oligodendroglia to axons through monocarboxylate transporter 1 may be critical for the survival of axons. This pathway has important implications both for the basic biology of the nervous system as well as for human neurologic disease. New insights into the role of oligodendroglial biology provide an exciting opportunity for revisions in nervous system biology, understanding myelin-based disorders and in therapeutics development.
MCT1; oligodendroglia; neurodegeneration; myelin; ALS; lactate
Mitochondria are cellular organelles that regulate commitment and execution of apoptosis. The intrinsic apoptotic pathway culminates in the permeabilization of the mitochondrial outer membrane and dismantling of the cell. Apoptosis of cancer cells is a favorable outcome when administering chemotherapeutic treatment yet the basis for why some cancers are sensitive to chemotherapy while others are not has historically been poorly understood. In this review, we present recent work that has demonstrated the importance of mitochondrial apoptotic priming, or how close a cell is to the threshold of apoptosis, in determining whether a cell will undergo apoptosis after chemotherapy treatment. Differential levels of apoptotic priming in tumors create bona fide opportunities and challenges for effective use of targeted and cytotoxic chemotherapies.
apoptosis; chemotherapy; mitochondrial apoptotic priming; chemotherapeutic window
Multifocal and recurrent epithelial tumors, originating from either dormant or de novo cancer cells, are major causes of morbidity and mortality. The age-dependent increase of cancer incidence has long been assumed to result from the sequential accumulation of cancer driving or facilitating mutations with induction of cellular senescence as a protective mechanism. However, recent evidence suggests that the initiation and development of epithelial cancer results from a close interplay with its altered tissue microenvironment, with chronic inflammation, stromal senescence, autophagy, and activation of cancer associated fibroblasts (CAFs) playing possible primary roles. We will discuss recent progress in these areas, and highlight how this understanding may be used for devising novel preventive and therapeutic approaches to the epithelial cancer problem.
stromal microenvironment; senescence; SASP; skin cancer; autophagy
Carcinogenesis is a mechanistically complex and variable process with a plethora of underlying genetic causes. Cancer development consists of a multitude of steps that occur progressively starting with initial driver mutation(s), to tumorigenesis, and ultimately metastasis. During these transitions, cancer cells accumulate a series of genetic alterations that confer upon the cells an unwarranted survival and proliferative advantage. During the course of development, however, cancer cells also encounter a physiologically ubiquitous cellular program that aims to eliminate damaged or abnormal cells: Apoptosis. Thus, it is essential that cancer cells acquire instruments to circumvent programmed cell death. Here we discuss emerging evidence indicating how cancer cells adopt various strategies to override apoptosis including amplifying the anti-apoptotic machinery, downregulating the pro-apoptotic program, or both.
BH3; Caspase; MOMP; Phosphorylation; Ubiquitination
•Lipophagy is a transcriptionally regulated process.•The lysosome as a sensor of lipophagy induction.•Nuclear receptors link lipophagy to lipid catabolism.
Autophagy is a catabolic pathway that has a fundamental role in the adaptation to fasting and primarily relies on the activity of the endolysosomal system, to which the autophagosome targets substrates for degradation. Recent studies have revealed that the lysosomal–autophagic pathway plays an important part in the early steps of lipid degradation. In this review, we discuss the transcriptional mechanisms underlying co-regulation between lysosome, autophagy, and other steps of lipid catabolism, including the activity of nutrient-sensitive transcription factors (TFs) and of members of the nuclear receptor family. In addition, we discuss how the lysosome acts as a metabolic sensor and orchestrates the transcriptional response to fasting.
Autophagy; lipophagy; lysosome; transcription factors; nuclear receptors; TP53; FOXOs; TFEB; mTORC1
Abscission is the last step of cytokinesis that leads to the physical separation of two daughter cells. An emerging picture is that abscission is a complex event that relies on changes in both lipid composition and cytoskeletal dynamics. These subcellular processes lead to the establishment of the abscission site and recruitment of the ESCRT-III protein complex to mediate the final separation event. It has become apparent that endocytic transport to the cleavage furrow during late cytokinesis mediates and coordinates lipid and cytoskeleton dynamics, thus playing a key role in abscission. Furthermore, new evidence suggests that endosomes may have additional roles in post-mitotic cellular events, such as midbody inheritance and degradation. Here, we highlight recent findings regarding the function of these endosomes in the regulation of cell division.
endosome; phosphoinositide; Rho kinase; ESCRT-III complex
Endosomal protein sorting governs the fate of many physiologically important proteins involved in a panoply of cellular functions. Recent discoveries have revealed a vital role for endosomally-localised branched actin patches in facilitating protein sorting. The formation of the actin patches has been shown to require the function of the WASH complex – the major endosomal actin polymerisation-promoting complex – that stimulates the activity of the ubiquitously expressed Arp2/3 complex. Another key component of the endosomal protein sorting machinery is the retromer complex. Studies now show that retromer mediates the recruitment of the WASH complex and its regulators to endosomes. In this review, the recent progress in understanding the role of the WASH complex along with retromer in endosomal protein sorting is discussed.
Retromer; WASH complex; endosome; sorting; actin; Fam21
Multiple types of cell death exist including necrosis, apoptosis, and autophagic cell death. The Drosophila ovary provides a valuable model to study the diversity of cell death modalities, and we review recent progress to elucidate these pathways. At least five distinct types of cell death occur in the ovary, and we focus on two that have been studied extensively. Cell death of mid-stage egg chambers uses a novel caspase-dependent pathway that involves autophagy, and triggers phagocytosis by surrounding somatic epithelial cells. For every egg, fifteen germline nurse cells undergo developmental programmed cell death, which occurs independently of most known cell death genes. These forms of cell death are strikingly similar to cell death observed in the germline of other organisms.
apoptosis; autophagy; Drosophila; oogenesis; ovary; programmed cell death
DNA organization and dynamics profoundly affect many biological processes
such as gene regulation and DNA repair. In this review, we present the latest
studies on DNA mobility in the context of DNA damage. Recent studies demonstrate
that DNA mobility is dramatically increased in the presence of double-strand
breaks (DSBs) in the yeast Saccharomyces cerevisiae. As a
consequence, chromosomes explore a larger nuclear volume, facilitating
homologous pairing but also increasing the rate of ectopic recombination.
Increased DNA dynamics is dependent on several homologous recombination (HR)
proteins and we are just beginning to understand how chromosome dynamics is
regulated after DNA damage.
DNA mobility; DNA repair; homologous recombination; double-strand break repair
Cells operate a signaling network termed unfolded protein response (UPR) to monitor protein-folding capacity in the endoplasmic reticulum (ER). IRE1 is an ER transmembrane sensor that activates UPR to maintain ER and cellular function. While mammalian IRE1 promotes cell survive, it can initiate apoptosis via decay of anti-apoptotic microRNAs. Convergent and divergent IRE1 characteristics between plants and animals underscore its significance in cellular homeostasis. This review provides an updated scenario of IRE1 signaling model, discusses emerging IRE1 sensing mechanisms, compares IRE1 features among species, and outlines exciting future directions in UPR research.
unfolded protein response; ER stress; IRE1; cell fate; protein quality control; membrane trafficking system
Desmosomes are intercellular junctions that anchor intermediate filaments to the plasma membrane, forming a supracellular scaffold that provides mechanical resilience to tissues. This anchoring function is accomplished by specialized members of the cadherin family and associated cytoskeletal linking proteins, which together form a highly organized membrane core flanked by mirror image cytoplasmic plaques. Due to the biochemical insolubility of desmosomes, the mechanisms that govern assembly of these components into a functional organelle remained elusive. Recently developed molecular reporters and live cell imaging approaches have provided powerful new tools to monitor this finely-tuned process in real time. Here we discuss studies that are beginning to decipher the machinery and regulation governing desmosome assembly and homeostasis in situ, and how these mechanisms are affected during disease pathogenesis.
cell junctions; desmosomal cadherins; desmoplakin; armadillo proteins
Around a century ago, the midbody was described as a structural assembly within the intercellular bridge during cytokinesis, which served to connect the two future daughter cells. The midbody has become the focus of intense investigation through the identification of a growing number of diverse cellular and molecular pathways that localize to the midbody and contribute to its cytokinetic functions ranging from selective vesicle trafficking, regulated microtubule, actin and ESCRT filament assembly and disassembly, and post-translational modification, such as ubiquitination. More recent studies revealed new and unexpected functions of midbodies that occur in post-mitotic cells. In this article, we provide a historical perspective, discuss exciting new roles for midbodies beyond their cytokinetic function and speculate on their potential contributions to pluripotency.
cytokinesis; abscission; midbody; asymmetry; stem cells; cell fates
Cortical domains are often specified by the local accumulation of active GTPases. Such domains can arise through spontaneous symmetry breaking, suggesting that GTPase accumulation occurs via positive feedback. Here, we focus on recent advances in fungal and plant cell models, where new work suggests that polarity-controlling GTPases develop only one “front” because GTPase clusters engage in a winner-takes-all competition. However, in some circumstances two or more GTPase domains can co-exist, and the basis for the switch from competition to coexistence remains an open question. Polarity GTPases can undergo oscillatory clustering and dispersal, suggesting that these systems contain negative feedback. Negative feedback may prevent polarity clusters from spreading too far, regulate the balance between competition and co-existence, and provide directional flexibility for cells tracking gradients.
Cdc42; Rac; Rop; GEF; GAP
The transmembrane domains (TMDs) of integral membrane proteins have emerged as major determinants of intracellular localization and transport in the secretory and endocytic pathways. Unlike sorting signals in the cytosolic domains, TMD sorting determinants are not conserved amino-acid sequences but physical properties such as length and hydrophilicity of the transmembrane span. The underlying sorting machinery is still poorly characterized but several mechanisms have been proposed, including TMD recognition by transmembrane sorting receptors and partitioning into membrane lipid domains. Here we review the nature of TMD sorting determinants and how they may dictate transmembrane protein localization and transport.
Transmembrane domains; protein sorting; protein traffic; lipid domains; transmembrane receptors; endomembrane system
In the cell, mRNAs and non-coding RNAs exist in association with proteins to form ribonucleoprotein (RNP) complexes. Regulation of RNP stability and function is achieved by alterations to the RNP through poorly understood mechanisms into which recent studies have now begun to provide insight. This emerging body of work identifies chemical modifications of RNPs at the RNA or protein level and ATP-dependent RNP remodeling by RNA helicases/RNA-dependent ATPases as central events that dictate RNA fate. Some RNP modifications serve as tags for recruitment of regulatory proteins, with RNP modifiers and recruited proteins analogous to the writers and readers of chromatin modification, respectively. This review highlights examples of in which RNP modification and ATP-dependent remodeling play key roles in the control of eukaryotic RNA fate, suggesting that we are only at the beginning of uncovering the multitude of ways in which RNP modification and remodeling impact RNA regulation.
RNA tailing; uridylation; ribonucleotidyltransferase; RNA modification; RNP modification; post-translational modification; RNA helicase; RNA decay
There are many mechanisms of lifespan extension, including the disruption of insulin/IGF-1 signaling, metabolism, translation, or feeding. Despite the disparate functions of these pathways, inhibition of each induces responses that buffer stress and damage. Here, emphasizing data from genetic analyses in C. elegans, we explore the effectors and upstream regulatory components of numerous cytoprotective mechanisms activated as major elements of longevity programs, including detoxification, innate immunity, proteostasis, and oxidative stress response. We show that their induction underpins longevity extension across functionally diverse triggers and across species. Intertwined with the evolution of longevity, cytoprotective pathways are coupled to the surveillance of core cellular components, with important implications in normal and aberrant responses to drugs, chemicals, and pathogens.
Cytoprotection; Hormesis; Detoxification; Stress; Longevity; Aging
One of the remarkable characteristics of higher organisms is the enormous assortment of cell types that emerge from a common genome. The immune system, with the daunting duty of detecting an astounding number of pathogens, and the nervous system with the equally bewildering task of perceiving and interpreting the external world, are the quintessence of cellular diversity. As we began to appreciate decades ago, achieving distinct expression programs among similar cell types cannot be accomplished solely by deterministic regulatory systems, but by the involvement of some type of stochasticity. In the last few years our understanding of these non-deterministic mechanisms is advancing, and this review will provide a brief summary of the current view of stochastic gene expression with focus on olfactory receptor gene choice, the epigenetic underpinnings of which recently began to emerge.
stochasticity; olfactory receptors; clustered protocadherins; antigen receptors; epigenetic mechanisms; nuclear architecture
PTEN loss drives many cancers and recent genetic studies reveal that often PTEN is antagonised at the protein level without alteration of DNA or RNA expression. This scenario can already cause malignancy since PTEN is haploinsufficient. We here review normally occurring mechanisms of PTEN protein regulation and discuss three processes where PTEN plasticity is needed: ischaemia, development and wound healing. These situations demand transient PTEN suppression while on the other hand cancer exploits them for continuous proliferation and survival advantages. Therefore increased understanding of PTEN plasticity may help us better interpret tumour development and ultimately lead to drug targets for PTEN supporting cancer therapy.
PTEN regulation; tumour suppressor; stroke; nerve regeneration