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F1000 Biol Rep. 2010; 2: 45.
Published online 2010 June 23. doi:  10.3410/B2-45
PMCID: PMC2950027

Autophagy of intracellular microbes and mitochondria: two sides of the same coin?

Abstract

Autophagy has become a biological paradigm of how eukaryotic cells, especially those that are long lived, maintain their vitality, control the quality of cytoplasmic organelles, and stay alive or die when growth factors are withdrawn and there is an energy or nutrient crisis. The role of autophagy has been extended to innate and adaptive immunity functions, which surpassed all initial expectations in terms of how immunity and autophagy are interconnected. Of particular interest at the moment is the growing appreciation of the similarity between how mitochondria and intracellular pathogens are handled by autophagy in its function of sanitizing the cytoplasm. An emerging framework from this may link the roots of cell defense against infection with cell longevity and programmed cell death.

Introduction and context

Autophagy is a fundamental biological process impacting a wide spectrum of human health and disease states [1], including cancer, neurodegeneration, myodegeneration, metabolic disorders (e.g., diabetes), aging, and innate and adaptive immunity [2]. The process of macroautophagy, or sensu stricto autophagy, can be viewed as a cytoplasmic homeostasis mechanism during which damaged or surplus intracellular organelles, supramacromolecular structures, large portions of the cytosol, and potentially toxic protein aggregates are sequestered into double membrane organelles termed autophagosomes [3]. Following the sequestration, the captured material is eliminated, when applicable, through maturation of autophagosomes into degradative organelles termed autolysosomes [3]. Very rapidly growing areas for autophagic investigations are the fields of immunity, infection, and inflammation. The field investigating the immunological roles of autophagy started with the appreciation that autophagy can clear intracellular microbes [4,5] and has been significantly broadened since. Today, we know that autophagy contributes to a wide panel of innate and adaptive immunity processes, ranging from effector and regulatory functions in response to innate immunity receptor agonists [2], to development of naïve T cell repertoires [6], and major histocompatibility complex (MHC) II [7] and MHC I antigen presentation [8]. The immune systems intersect broadly with autophagy, posing the question of whether the two processes are connected in an evolutionarily ancient manner (thus explaining why autophagy is hardwired into so many immunological processes), or whether it is simply a convergent use of a versatile and successful process. The former model is more likely, a view that is supported by the latest wave of studies indicating a parallel between autophagy of mitochondria (a process termed mitophagy) and autophagy of intracellular microbes (a process known as xenophagy).

Major recent advances

When viewed as a crude biomass degradative process, autophagy can be a life-saving, cell-autonomous source of nutrients and energy produced by autodigestion of the cytosol under conditions where cells are limited for growth due to a lack of nutrients or growth factors. In its more sophisticated but also pro-survival manifestations, autophagy removes protein aggregates too large for proteasomal disposal, trims the amount and quality of intracellular compartments (e.g., endoplasmic reticulum) and disposes of damaged organelles, such as irreversibly depolarized or leaky mitochondria, that sporadically but relentlessly occur in all cells. The process of mitophagy, along with other aspects of quality control functions of autophagy, ensures survival and internal rejuvenation of long lived cells such as neurons, myocytes, macrophages, and so on. Furthermore, mitochondrial removal via autophagy takes place during development and cellular differentiation, as in the case of red blood cells [9] and T cell maturation [10]. Thus, mitophagy is key to both the longevity and proper differentiation and function of cells. The autophagy of stress-damaged mitochondria is based on the ubiquitination of proteins (e.g., voltage-dependent anion channel VDAC1) on depolarized mitochondria via the E3 ligase Parkin [11], which tags the mitochondria with poly-ubiquitinated chains. These are then recognized by the autophagic adapter protein p62 (SQSTM1) [12], which has a motif (WXXL) known as LIR (for LC3-interacting region) that allows p62 to bind to LC3 (ATG8), a marquee protein for nascent autophagosomal membranes. The net result is that damaged mitochondria are ‘reeled in’ by the adapter p62 into the autophagic organelles for clearance [11] (Figure 1A).

Figure 1.
Conservation of the process of autophagic removal of mitochondria and intracellular bacteria

Intriguingly, a similar mechanism has been nearly simultaneously described for autophagic removal of a number of intracellular bacteria (Figure 1B) and potentially other microbes. Sindbis virus capsid is recognized by p62 and targeted to autophagosomes protecting infected neurons from virus-induced pathology [13]. Polyubiquitin-decorated Listeria (rendered defenseless by the loss of ActA) is recognized by p62 and delivered to autophagosomes for degradation [14]. The perforated phagosomes during escape of Shigella into the cytosol are also captured for autophagy by polyubiquitin-p62-LC3 bridges [15]. Interestingly, when autophagic clearance of damaged Shigella phagosomal remnants was obstructed, TRAF6 (known to directly interact with p62), led to inflammatory signaling and cell death [15], suggesting a potential scenario where if the pathogen or signals associated with its presence in the cytosol are not eliminated by autophagy, a second stage response kicks in leading to elimination of the chronically infected cell, thus limiting infection spread by cell death. The adapter p62 is not the only participant in these processes. Whereas Salmonella can be autophagically eliminated in a similar process using p62 [16], another LC3-interacting adapter, nuclear dot protein 52 (NDP52), is a key player in removing cytosolic Salmonella [17]. Apart from Salmonella, NDP52 plays a role in autophagy of cytosolic Streptococcus pyogenes [17]. In some cases, as with Mycobacterium tuberculosis that resides inside the phagosomes in infected macrophages, it is not the microbe that is captured by p62 and delivered to autophagosomes, but rather p62 plays a role in antimicrobial action of autophagy in a different, mirror image process [18]. In this case, p62 collects cytoplasmic proteins, such as ubiquitin or ribosomal precursor proteins, and delivers them to autophagosomes where they are digested into smaller peptides within the autolysosomes. This autolysosomal peptide cargo is then delivered to mycobacterial phagosomes. It turns out that ribosomal or ubiquitin fragments proteolytically generated in autophagic organelles from otherwise innocuous precursor cytoplasmic proteins possess antimicrobial properties and help kill intracellular M. tuberculosis [18].

Future directions

The similarity of the molecular processes involved in autophagic targeting of mitochondria and microbes suggests a potentially common evolutionary root of mitophagy and xenophagy. Since mitochondria evolved from a Rickettsia-like α-protobacterium, it is possible that the processes we recognize today as mitophagy or xenophagy (and perhaps autophagy altogether) may have diverged from a common primordial system (proto-autophagy) in early eukaryotic cells that had to deal with invasion by intracellular microbes. If this model is correct, understanding the nature of interactions between cells and mitochondria may help understand immunological roles of autophagy. Likewise, cell survival and programmed cell death processes (dependent on mitochondria), of high significance for many normal or pathological states such as neurodegeneration, cancer, and aging, may conceptually and mechanistically benefit from understanding the common proto-autophagy roots of mitophagy and autophagic elimination of microbes.

Acknowledgments

This work was supported by grants RC1AI086845, AI069345, and AI42999 from the National Institutes of Health, 107160-44-RGRL from the American Foundation for AIDS Research (amfAR), a Bill & Melinda Gates Grand Challenge Explorations grant, and a grant from the Crohn’s and Colitis Foundation of America.

Abbreviations

ATG8
autophagy-related protein 8
MHC
major histocompatibility complex
NDP52
nuclear dot protein 52
SQSTM1
sequestosome 1
TRAF6
tumor necrosis factor receptor-associated factor 6

Notes

The electronic version of this article is the complete one and can be found at: http://f1000.com/reports/b/2/45

Notes

Competing Interests

The author declares that he has no competing interests.

References

1. Mizushima N, Levine B, Cuervo AM, Klionsky DJ. Autophagy fights disease through cellular self-digestion. Nature. 2008;451:1069–75. doi: 10.1038/nature06639. [PMC free article] [PubMed] [Cross Ref]
2. Deretic V, Levine B. Autophagy, immunity, and microbial adaptations. Cell Host Microbe. 2009;5:527–49. doi: 10.1016/j.chom.2009.05.016. [PMC free article] [PubMed] [Cross Ref]
3. Mizushima N, Yoshimori T, Levine B. Methods in mammalian autophagy research. Cell. 2010;140:313–26. doi: 10.1016/j.cell.2010.01.028. [PMC free article] [PubMed] [Cross Ref]
4. Gutierrez MG, Master SS, Singh SB, Taylor GA, Colombo MI, Deretic V. Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages. Cell. 2004;119:753–66. doi: 10.1016/j.cell.2004.11.038. [PubMed] [Cross Ref] F1000 Factor 6.5 Must Read
Evaluated by Suresh Subramani 25 Nov 2004, Gerald Pier 21 Dec 2004, Michael Gold 23 Dec 2004
5. Nakagawa I, Amano A, Mizushima N, Yamamoto A, Yamaguchi H, Kamimoto T, Nara A, Funao J, Nakata M, Tsuda K, Hamada S, Yoshimori T. Autophagy defends cells against invading group A Streptococcus. Science. 2004;306:1037–40. doi: 10.1126/science.1103966. [PubMed] [Cross Ref] F1000 Factor 4.8 Must Read
Evaluated by Daniel Klionsky 09 Nov 2004, Suresh Subramani 25 Nov 2004
6. Nedjic J, Aichinger M, Emmerich J, Mizushima N, Klein L. Autophagy in thymic epithelium shapes the T-cell repertoire and is essential for tolerance. Nature. 2008;455:396–400. doi: 10.1038/nature07208. [PubMed] [Cross Ref] F1000 Factor 6.8 Must Read
Evaluated by Vojo Deretic 27 Aug 2008, Edward Collins 03 Oct 2008, Thomas Huenig 09 Oct 2008, Colin Watts 17 Oct 2008
7. Jagannath C, Lindsey DR, Dhandayuthapani S, Xu Y, Hunter RL, Jr, Eissa NT. Autophagy enhances the efficacy of BCG vaccine by increasing peptide presentation in mouse dendritic cells. Nat Med. 2009;15:267–76. doi: 10.1038/nm.1928. [PubMed] [Cross Ref] F1000 Factor 8.1 Exceptional
Evaluated by Vojo Deretic 04 Mar 2009, Thomas W von Geldern 24 Mar 2009, George Yap 09 Apr 2009
8. English L, Chemali M, Duron J, Rondeau C, Laplante A, Gingras D, Alexander D, Leib D, Norbury C, Lippé R, Desjardins M. Autophagy enhances the presentation of endogenous viral antigens on MHC class I molecules during HSV-1 infection. Nat Immunol. 2009;10:480–7. doi: 10.1038/ni.1720. [PubMed] [Cross Ref] F1000 Factor 6.0 Must Read
Evaluated by George Yap 09 Apr 2009
9. Sandoval H, Thiagarajan P, Dasgupta SK, Schumacher A, Prchal JT, Chen M, Wang J. Essential role for Nix in autophagic maturation of erythroid cells. Nature. 2008;454:232–5. doi: 10.1038/nature07006. [PMC free article] [PubMed] [Cross Ref] F1000 Factor 8.1 Exceptional
Evaluated by Richard Youle 13 May 2008, Christoph Borner 27 May 2008, Daniel Klionsky 21 Aug 2008
10. Pua HH, Guo J, Komatsu M, He YW. Autophagy is essential for mitochondrial clearance in mature T lymphocytes. J Immunol. 2009;182:4046–55. doi: 10.4049/jimmunol.0801143. [PubMed] [Cross Ref]
11. Geisler S, Holmstrom KM, Skujat D, Fiesel FC, Rothfuss OC, Kahle PJ, Springer W. PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat Cell Biol. 2010;12:119–31. doi: 10.1038/ncb2012. [PubMed] [Cross Ref] F1000 Factor 6.0 Must Read
Evaluated by Ivan Dikic 16 Feb 2010
12. Kirkin V, Lamark T, Sou YS, Bjørkøy G, Nunn JL, Bruun JA, Shvets E, McEwan DG, Clausen TH, Wild P, Bilusic I, Theurillat JP, Øvervatn A, Ishii T, Elazar Z, Komatsu M, Dikic I, Johansen T. A role for NBR1 in autophagosomal degradation of ubiquitinated substrates. Mol Cell. 2009;33:505–16. doi: 10.1016/j.molcel.2009.01.020. [PubMed] [Cross Ref] F1000 Factor 3.0 Recommended
Evaluated by Daniel Klionsky 01 Jun 2009
13. Orvedahl A, Macpherson S, Sumpter R, Jr, Talloczy Z, Zou Z, Levine B. Autophagy protects against Sindbis virus infection of the central nervous system. Cell Host Microbe. 2010;7:115–27. doi: 10.1016/j.chom.2010.01.007. [PMC free article] [PubMed] [Cross Ref]
14. Yoshikawa Y, Ogawa M, Hain T, Yoshida M, Fukumatsu M, Kim M, Mimuro H, Nakagawa I, Yanagawa T, Ishii T, Kakizuka A, Sztul E, Chakraborty T, Sasakawa C. Listeria monocytogenes ActA-mediated escape from autophagic recognition. Nat Cell Biol. 2009;11:1233–40. doi: 10.1038/ncb1967. [PubMed] [Cross Ref] Evaluated by 6.0 Must Read
Evaluated by Pascale Cossart 28 Oct 2009
15. Dupont N, Lacas-Gervais S, Bertout J, Paz I, Freche B, Van Nhieu GT, van der Goot FG, Sansonetti PJ, Lafont F. Shigella phagocytic vacuolar membrane remnants participate in the cellular response to pathogen invasion and are regulated by autophagy. Cell Host Microbe. 2009;6:137–49. doi: 10.1016/j.chom.2009.07.005. [PubMed] [Cross Ref] F1000 Factor 6.0 Must Read
Evaluated by Vojo Deretic 20 Nov 2009
16. Zheng YT, Shahnazari S, Brech A, Lamark T, Johansen T, Brumell JH. The adaptor protein p62/SQSTM1 targets invading bacteria to the autophagy pathway. J Immunol. 2009;183:5909–16. doi: 10.4049/jimmunol.0900441. [PubMed] [Cross Ref]
17. Thurston TL, Ryzhakov G, Bloor S, von Muhlinen N, Randow F. The TBK1 adaptor and autophagy receptor NDP52 restricts the proliferation of ubiquitin-coated bacteria. Nat Immunol. 2009;10:1215–21. doi: 10.1038/ni.1800. [PubMed] [Cross Ref] F1000 Factor 3.0 Recommended
Evaluated by Daniel Klionsky 13 Nov 2009
18. Ponpuak M, Davis AS, Roberts EA, Delgado MA, Dinkins C, Zhao Z, Virgin HW, 4th, Kyei GB, Johansen T, Vergne I, Deretic V. Delivery of cytosolic components by autophagic adapter portein p62 endows autophagosomes with unique antimicrobial properties. Immunity. 2010;32:329–41. doi: 10.1016/j.immuni.2010.02.009. [PMC free article] [PubMed] [Cross Ref] F1000 Factor 6.0 Must Read
Evaluated by Michel Desjardins 11 Mar 2010

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