HÜCRE KORUYUCU BİR MEKANİZMA: OTOFAJİ

Yıl 2017, Cilt: 26 Sayı: 3, 275 - 281, 01.12.2017

Narin Liman Duygu Cemre Suna

Öz

Otofaji (kendini yeme) hasarlı hücresel proteinleri ve
organelleri ortadan kaldıran evrimsel bir süreçtir.
Otofaji uyarılınca bozunuma uğrayan sitoplazma ve
organeller veziküller içine alınır. Şekillenen veziküller
mayalarda vakuole, memeli hücrelerinde lizozoma gönderilir. Açlık veya oksidatif stres gibi durumlarda ya da
normal koşullar altında makromoleküllerin bozunumu
ve besin dengesinin sağlanması otofaji aracılığıyla düzenlenir. Ökaryotik hücrelerde otofaji, oluşma şekline
göre makro-otofaji, mikro-otofaji ve şaperon aracılı
otofaji olarak sınıflandırılır. Bunların hepsi lizozomda
sitosolik bileşenlerin proteolitik bozunmasını teşvik
eder ve otofajiye bağlı genler ve bunlarla ilişkili enzimler aracılığıyla düzenlenirler. Makro-otofaji ve mikrootofaji bağımlı lizozomal/vakuoler yıkım süreci ya seçici olmaz (non-selektif) ya da seçicidir (selektif).
Şaperon aracılı otofaji yanlış katlanmış veya yanlışlıkla
oluşturulmuş sitosolik proteinleri indirgemek için kullanılan bir seçici otofajidir. Seçici olmayan makrootofajide sitoplazma otofagozom oluşumuyla, mikrootofajide ise çözünebilir intrasellüler substratlar boru
biçimindeki invaginasyonlarla lizozom/vakuol içine
alınır. Seçici makro- ya da mikro-otofaji sayısı artan ya
da hasar görmüş olan çeşitli organeller ile invaziv mikropları hedef alır. Bu durumda otofaji kargo içeriğine
göre retikulofaji veya ERfaji, pekzofaji, mitofaji, lipofaji,
zimofaji, nükleofaji, ribofaji, agrefaji ve ksenofaji gibi
özel isimlerle tanımlanır. Bu derlemede doğru hücresel
fonksiyonları korumak için hasarlı organelleri, protein
yığınlarını ve hücre içi patojenleri yok eden bir
sitoprotektif program olarak işlev gören otofaji ele alınmıştır.

Anahtar Kelimeler

Otofaji, lizozom, vakuol, ULK1, TOR

A Cytoprotective Mechanism: Autophagy

Öz

Autophagy (self-eating) is an evolutionary process that
removes damaged cellular proteins and organelles.
When autophagy is induced, degrading cytoplasm and
organelles are taken up into vesicles. . These vesicles are
sent to the vacuolated or lysosomes in the yeast and
mammalian cells, respectively. Provision of degradation
of macromolecules and nutrient balance under stress
conditions, such as starvation or oxidative stress or
under normal conditions, is regulated by autophagy. In
eukaryotic cells, autophagy is classified as macroautophagy, micro-autophagy and chaperone-mediated
autophagy according to the formation pattern. All of
these promote the proteolytic degradation of cytosolic
components in the lysosome and are regulated by
autophage-linked genes and their associated enzymes.
Macro-autophagy and micro-autophagy dependent
lysosomal/vacuolar degradation processes are either
non-selective or selective (selective). Chaperonemediated autophagy is a selective autophagy used to
reduce unfolded or misfolded cytosolic proteins. In the
non-selective macro-autophagy, the cytoplasm is
incorporated into the lysosome/vacuole by
autophagosome, while in the micro-autophagy the
soluble intracellular substrates are introduced into the
lysosome/vacuole via tubular invaginations. The
selective macro- or micro-autophagy target invasive
microorganisms with various organelles that are either
increased in number or damaged. In this case,
autophagy is defined by special names such as
reticulophagy or ERphagy, pexophagy, mitophagy,
lipophagy, zimophagy, nucleophagy, ribophagy,
aggrephagy and ksenophagy, according to the contents
of the cargo. This review focuses on autophagy that
functions as a cytoprotective program that destroys
damaged organelles, protein deposits and intracellular
pathogens in order to preserve the correct cellular
functions.

Anahtar Kelimeler

Autophagy, lysosome, vacuole, ULK1, TOR

Kaynakça

• 1. Deter RL, De Duve C. Influence of glucagon, an inducer of cellular autophagy, on some physical properties of rat liver lysosomes. J Cell Biol 1967; 33:437–449.
• 2. Ferraro E, Cecconi F. Autophagic and apoptotic response to stress signals in mammalian cells. Arch Biochem Biophys 2007; 462:210–219.
• 3. Mizushima N. Autophagy: process and function. Genes Dev 2007; 21:2861–2873.
• 4. Murrow L, Debnath J. Autophagy as a stress response and quality control mechanism— implications for cell injury and human disease. Annu Rev Pathol 2013; 8:105–137.
• 5. Kraft C, Peter M, Hofmann K. Selective autophagy: ubiquitin-mediated recognition and beyond. Nature cell biology 2010; 12:836–841.
• 6. Mizushima N, Yoshimori T, Ohsumi Y. The role of Atg proteins in autophagosome formation. Annu Rev Cell Dev Biol 2011; 27:107–132.
• 7. Klionsky DJ. The molecular machinery of autophagy: unanswered questions. J Cell Sci 2005; 118:7–18.
• 8. Massey AC, Zhang C, Cuervo AM. Chaperonemediated autophagy in aging and disease. Curr Top Dev Biol 2006; 73:205–235.
• 9. Xie Z, Klionsky DJ. Autophagosome formation: core machinery and adaptations. Nat Cell Biol 2007; 9: 1102–1109.
• 10. Lee J, Giordano S, Zhang J. Autophagy, mitochondria and oxidative stress: cross-talk and redox signalling. Biochem J 2012; 441:523–540.
• 11. Mizushima N, Ohsumi Y, Yoshimori T. Autophagosome formation in mammalian cells. Cell Struct Funct 2002; 27:421–429.
• 12. Klionsky DJ, Cuervo AM, Dunn WA, et al. How shall i eat thee? Autophagy 2007; 3:413–416.
• 13. Li WW, Li J, Bao JK. Microautophagy: lesser-known self-eating. Cell Mol Life Sci 2012; 69:1125–1136.
• 14. Wada Y, Sun-Wada G-H, Kawamura N, Aoyama M. Role of autophagy in embryogenesis. Curr Opin Genet Dev 2014; 27:60–66.
• 15. Aburto MR, Hurlé JM, Varela-Nieto I, Magariños M. Autophagy during vertebrate development. Cell 2012; 1:428–448.
• 16. Overholtzer M., Mailleux A.A., Mouneimne G, et al. A nonapoptotic cell death process, entosis, that occurs by cell-in-cell invasion. Cell 2007; 131:966–979.
• 17. Axe EL, Walker SA, Manifava M, et al. Autophagosome formation from membrane compartments enriched in phosphatidylinositol 3- phosphate and dynamically connected to the endoplasmic reticulum. J Cell Biol 2008; 182:685– 701.
• 18. Simonsen A, Tooze SA. Coordination of membrane events during autophagy by multiple class III PI3– kinase complexes. J Cell Biol 2009; 186:773–782.
• 19. Pavel M, Rubinsztein DC. Mammalian autophagy and the plasma membrane. FEBS J 2017; 284:672– 679.
• 20. Rodriguez-Rocha H, Garcia-Garcia A, Panayiotidis MI, Franco R. DNA damage and autophagy. Mutat Res 2011; 711: 158–166.
• 21. Ganley IG, Lam DH, Wang J, et al. ULK1·ATG13·FIP200 complex mediates mTOR signaling and is essential for autophagy. J Biol Chem 2009; 284:12297–12305.
• 22. Mercer CA, Kaliappan A, Dennis PB. A novel, human Atg13 binding protein, Atg101, interacts with ULK1 and is essential for macroautophagy. Autophagy 2009; 5:649–662.
• 23. He C, Klionsky DJ. Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet 2009; 43:67–93.
• 24. Kim J, Kundu M, Viollet B, Guan KL, AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 2011; 13:132 –141.
• 25. Suzuki K, Ohsumi Y. Molecular machinery of autophagosome formation in yeast, Saccharomyces cerevisiae. FEBS Lett 2007; 581:2156–2161.
• 26. Suzuki K, Kubota Y, Sekito T, Ohsumi Y. Hierarchy of Atg proteins in pre-autophagosomal structure organization. Genes Cells 2007; 12:209–218.
• 27. Kamada Y, Yoshino K, Kondo C, et al. Tor directly controls the Atg1 kinase complex to regulate autophagy. Mol Cell Biol 2010; 30:1049–1058.
• 28. Hurley JH, Young LN. Mechanism of autophagy initiaton. Annu Rev Biochem 2017; 86:225–244.
• 29. Jung CH, Jun CB, Ro SH, et al. ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. Mol Biol Cel 2009; 20:1992– 2003.
• 30. Chan EY, Longatti A, McKnight NC, Tooze SA. Kinase -inactivated ULK proteins inhibit autophagy via their conserved C-terminal domains using an Atg13 -independent mechanism. Mol Cell Biol 2009; 29:157–171.
• 31. Hosokawa N, Hara T, Kaizuka T, et al. Nutrientdependent mTORC1 association with the ULK1- Atg13-FIP200 complex required for autophagy. Mol Biol Cell 2009; 20:1981–1991.
• 32. Hara T, Takamura A, Kishi C, et al. FIP200, a ULKinteracting protein, is required for autophagosome formation in mammalian cells. J Cell Biol 2008; 181:497–510.
• 33. Bento CF, Renna M, Ghislat G, et al. Mammalian autophagy: How does it work? Annu Rev Biochem 2016; 85:685–713.
• 34. Amaya C, Marcelo C, Fader M, Colombo MI. Autophagy and proteins involved in vesicular trafficking. FEBS Letters 2015; 589:3343–3353.
• 35. Reggiori F, Ungermann C. Autophagosome maturation and fusion. J Mol Biol 2017; 429:486– 496.
• 36. Feng Y, Klionsky DJ. Autophagic membrane delivery through ATG9. Cell 2017; 27:161–162.
• 37. Füllgrabe J, Klionsky DJ, Joseph B. The return of the nucleus: transcriptional and epigenetic control of autophagy. Nat Rev Mol Cell Biol 2014; 15:65–74.
• 38. deDuve C, Wattiaux R. Functions of lysosomes. Annu Rev Physiol 1966; 28: 435–492.
• 39. Castro-Obregon S. The discovery of lysosomes and autophagy. Nature Education 2010; 3:49.
• 40. Uttenweiler A, Schwarz H, Mayer A. Microautophagic vacuole invagination requires calmodulin in a Ca2+ independent function. J Biol Chem 2005; 280:33289–33297.
• 41. Müller O, Sattler T, Flötenmeyer M, et al. Autophagic tubes: Vacuolar invaginations involved in lateral membrane sorting and inverse vesicle budding - laboratorium der Max-Planck. J Cell Biol 2000; 151:519–528.
• 42. Sattler T, Mayer A. Cell-Free Reconstitution of Microautophagic Vacuole Invagination and Vesicle Formation. J Cell Biol 2000; 151:529–538.
• 43. Yang Z, Klionsky DJ. Permeases recycle amino acids resulting from autophagy. Autophagy 2007; 3:149– 150.
• 44. Levine B, Mizushima N, Virgin HW. Autophagy in immunity and inflammation. Nature 2011; 469:323 –335.
• 45. Kon M, Cuervo AM. Chaperone-mediated autophagy in health and disease. FEBS Letters 2010; 584:1399 -1404