#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

A Role for Macro-ER-Phagy in ER Quality Control


ER-quality control (ERQC) ensures delivery of “native” proteins through the secretory pathway. Currently, ER-associated degradation (ERAD), which delivers misfolded proteins for degradation by the proteasome, is considered a major ERQC pathway, with autophagy as its backup. Until now, the role of autophagy, which shuttles cellular components for degradation in the lysosome through autophagosomes (APs), in ERQC was ill defined. Recently, the process of ER degradation induced by ER stress was defined as micro-ER-phagy, which does not require autophagic machinery and does not pass through APs. Here, we characterize the macro-ER-phagy pathway, which delivers excess membrane proteins for degradation in the lysosome, as a novel ERQC pathway. This pathway functions in the absence of cellular or ER stress and can be further induced by overexpression of a single integral-membrane protein. Unlike the micro-ER-phagy pathway, the marco-ER-phagy pathway requires core autophagy-specific proteins, Atgs, and Ypt/Rab GTPases. In addition, for the first time, the function of the only membrane core Atg, Atg9, was uncoupled from that of the other core Atgs. Whereas Atg9 plays a role in the assembly of ER-to-autophagy membranes (ERAM), other core Atgs and Ypt1 assemble the Atg-protein complex on ERAM to form the pre-autophagosomal structure.


Vyšlo v časopise: A Role for Macro-ER-Phagy in ER Quality Control. PLoS Genet 11(7): e32767. doi:10.1371/journal.pgen.1005390
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005390

Souhrn

ER-quality control (ERQC) ensures delivery of “native” proteins through the secretory pathway. Currently, ER-associated degradation (ERAD), which delivers misfolded proteins for degradation by the proteasome, is considered a major ERQC pathway, with autophagy as its backup. Until now, the role of autophagy, which shuttles cellular components for degradation in the lysosome through autophagosomes (APs), in ERQC was ill defined. Recently, the process of ER degradation induced by ER stress was defined as micro-ER-phagy, which does not require autophagic machinery and does not pass through APs. Here, we characterize the macro-ER-phagy pathway, which delivers excess membrane proteins for degradation in the lysosome, as a novel ERQC pathway. This pathway functions in the absence of cellular or ER stress and can be further induced by overexpression of a single integral-membrane protein. Unlike the micro-ER-phagy pathway, the marco-ER-phagy pathway requires core autophagy-specific proteins, Atgs, and Ypt/Rab GTPases. In addition, for the first time, the function of the only membrane core Atg, Atg9, was uncoupled from that of the other core Atgs. Whereas Atg9 plays a role in the assembly of ER-to-autophagy membranes (ERAM), other core Atgs and Ypt1 assemble the Atg-protein complex on ERAM to form the pre-autophagosomal structure.


Zdroje

1. Ellgaard L, Helenius A (2003) Quality control in the endoplasmic reticulum. Nature reviews Molecular cell biology 4: 181–191. 12612637

2. Guerriero CJ, Brodsky JL (2012) The delicate balance between secreted protein folding and endoplasmic reticulum-associated degradation in human physiology. Physiological reviews 92: 537–576. doi: 10.1152/physrev.00027.2011 22535891

3. Nakatsukasa K, Brodsky JL (2008) The recognition and retrotranslocation of misfolded proteins from the endoplasmic reticulum. Traffic 9: 861–870. doi: 10.1111/j.1600-0854.2008.00729.x 18315532

4. Vembar SS, Brodsky JL (2008) One step at a time: endoplasmic reticulum-associated degradation. Nature reviews Molecular cell biology 9: 944–957. doi: 10.1038/nrm2546 19002207

5. Walter P, Ron D (2011) The unfolded protein response: from stress pathway to homeostatic regulation. Science 334: 1081–1086. doi: 10.1126/science.1209038 22116877

6. Parzych KR, Klionsky DJ (2014) An overview of autophagy: morphology, mechanism, and regulation. Antioxidants & redox signaling 20: 460–473.

7. Feng Y, He D, Yao Z, Klionsky DJ (2014) The machinery of macroautophagy. Cell research 24: 24–41. doi: 10.1038/cr.2013.168 24366339

8. Ohsumi Y (2014) Historical landmarks of autophagy research. Cell research 24: 9–23. doi: 10.1038/cr.2013.169 24366340

9. Manjithaya R, Nazarko TY, Farre JC, Subramani S (2010) Molecular mechanism and physiological role of pexophagy. FEBS letters 584: 1367–1373. doi: 10.1016/j.febslet.2010.01.019 20083110

10. Suzuki K (2013) Selective autophagy in budding yeast. Cell death and differentiation 20: 43–48. doi: 10.1038/cdd.2012.73 22705847

11. Lamb CA, Yoshimori T, Tooze SA (2013) The autophagosome: origins unknown, biogenesis complex. Nature reviews Molecular cell biology 14: 759–774. 24201109

12. Yorimitsu T, Klionsky DJ (2007) Endoplasmic reticulum stress: a new pathway to induce autophagy. Autophagy 3: 160–162. 17204854

13. Houck SA, Ren HY, Madden VJ, Bonner JN, Conlin MP, et al. (2014) Quality control autophagy degrades soluble ERAD-resistant conformers of the misfolded membrane protein GnRHR. Molecular cell 54: 166–179. doi: 10.1016/j.molcel.2014.02.025 24685158

14. Bernales S, Schuck S, Walter P (2007) ER-phagy: selective autophagy of the endoplasmic reticulum. Autophagy 3: 285–287. 17351330

15. Schuck S, Gallagher CM, Walter P (2014) ER-phagy mediates selective degradation of endoplasmic reticulum independently of the core autophagy machinery. Journal of cell science 127: 4078–4088. doi: 10.1242/jcs.154716 25052096

16. Cebollero E, Reggiori F, Kraft C (2012) Reticulophagy and ribophagy: regulated degradation of protein production factories. International journal of cell biology 2012: 182834. doi: 10.1155/2012/182834 22481944

17. Lipatova Z, Shah AH, Kim JJ, Mulholland JW, Segev N (2013) Regulation of ER-phagy by a Ypt/Rab GTPase module. Molecular biology of the cell 24: 3133–3144. doi: 10.1091/mbc.E13-05-0269 23924895

18. Segev N (2011) Coordination of intracellular transport steps by GTPases. Seminars in cell & developmental biology 22: 33–38.

19. Segev N (2001) Ypt and Rab GTPases: insight into functions through novel interactions. Current opinion in cell biology 13: 500–511. 11454458

20. Stenmark H (2009) Rab GTPases as coordinators of vesicle traffic. Nature reviews Molecular cell biology 10: 513–525. doi: 10.1038/nrm2728 19603039

21. Jedd G, Richardson C, Litt R, Segev N (1995) The Ypt1 GTPase is essential for the first two steps of the yeast secretory pathway. The Journal of cell biology 131: 583–590. 7593181

22. Lipatova Z, Belogortseva N, Zhang XQ, Kim J, Taussig D, et al. (2012) Regulation of selective autophagy onset by a Ypt/Rab GTPase module. Proceedings of the National Academy of Sciences of the United States of America 109: 6981–6986. doi: 10.1073/pnas.1121299109 22509044

23. Lipatova Z, Segev N (2014) Ypt/Rab GTPases regulate two intersections of the secretory and the endosomal/lysosomal pathways. Cellular logistics 4: e954870. 25610722

24. Chen Y, Zhou F, Zou S, Yu S, Li S, et al. (2014) A Vps21 endocytic module regulates autophagy. Molecular biology of the cell 25: 3166–3177. doi: 10.1091/mbc.E14-04-0917 25143401

25. Singer-Kruger B, Stenmark H, Dusterhoft A, Philippsen P, Yoo JS, et al. (1994) Role of three rab5-like GTPases, Ypt51p, Ypt52p, and Ypt53p, in the endocytic and vacuolar protein sorting pathways of yeast. The Journal of cell biology 125: 283–298. 8163546

26. Polupanov AS, Nazarko VY, Sibirny AA (2011) CCZ1, MON1 and YPT7 genes are involved in pexophagy, the Cvt pathway and non-specific macroautophagy in the methylotrophic yeast Pichia pastoris. Cell biology international 35: 311–319. doi: 10.1042/CBI20100547 21155714

27. Lewis MJ, Nichols BJ, Prescianotto-Baschong C, Riezman H, Pelham HR (2000) Specific retrieval of the exocytic SNARE Snc1p from early yeast endosomes. Molecular biology of the cell 11: 23–38. 10637288

28. Zanetti G, Pahuja KB, Studer S, Shim S, Schekman R (2012) COPII and the regulation of protein sorting in mammals. Nature cell biology 14: 20–28.

29. Reggiori F, Klionsky DJ (2013) Autophagic processes in yeast: mechanism, machinery and regulation. Genetics 194: 341–361. doi: 10.1534/genetics.112.149013 23733851

30. Lipatova Z, Hain AU, Nazarko VY, Segev N (2015) Ypt/Rab GTPases: Principles learned from yeast. Critical reviews in biochemistry and molecular biology: 1–9.

31. Thomas JD, Zhang YJ, Wei YH, Cho JH, Morris LE, et al. (2014) Rab1A is an mTORC1 activator and a colorectal oncogene. Cancer cell 26: 754–769. doi: 10.1016/j.ccell.2014.09.008 25446900

32. Cheong H, Nair U, Geng J, Klionsky DJ (2008) The Atg1 kinase complex is involved in the regulation of protein recruitment to initiate sequestering vesicle formation for nonspecific autophagy in Saccharomyces cerevisiae. Molecular biology of the cell 19: 668–681. 18077553

33. Nakatogawa H, Suzuki K, Kamada Y, Ohsumi Y (2009) Dynamics and diversity in autophagy mechanisms: lessons from yeast. Nature reviews Molecular cell biology 10: 458–467. doi: 10.1038/nrm2708 19491929

34. Weidberg H, Shvets E, Elazar Z (2011) Biogenesis and cargo selectivity of autophagosomes. Annual review of biochemistry 80: 125–156. doi: 10.1146/annurev-biochem-052709-094552 21548784

35. Munakata N, Klionsky DJ (2010) "Autophagy suite": Atg9 cycling in the cytoplasm to vacuole targeting pathway. Autophagy 6: 679–685. 20543572

36. Nagy P, Hegedus K, Pircs K, Varga A, Juhasz G (2014) Different effects of Atg2 and Atg18 mutations on Atg8a and Atg9 trafficking during starvation in Drosophila. FEBS letters 588: 408–413. doi: 10.1016/j.febslet.2013.12.012 24374083

37. d'Enfert C, Barlowe C, Nishikawa S, Nakano A, Schekman R (1991) Structural and functional dissection of a membrane glycoprotein required for vesicle budding from the endoplasmic reticulum. Molecular and cellular biology 11: 5727–5734. 1922074

38. Segev N (1991) Mediation of the attachment or fusion step in vesicular transport by the GTP-binding Ypt1 protein. Science 252: 1553–1556. 1904626

39. Fu L, Sztul E (2003) Traffic-independent function of the Sar1p/COPII machinery in proteasomal sorting of the cystic fibrosis transmembrane conductance regulator. The Journal of cell biology 160: 157–163. 12538638

40. Davies BA, Azmi IF, Katzmann DJ (2009) Regulation of Vps4 ATPase activity by ESCRT-III. Biochemical Society transactions 37: 143–145. doi: 10.1042/BST0370143 19143619

41. Klionsky DJ, Cuervo AM, Seglen PO (2007) Methods for monitoring autophagy from yeast to human. Autophagy 3: 181–206. 17224625

42. Lipatova Z, Segev N (2012) A Ypt/Rab GTPase module makes a PAS. Autophagy 8: 1271–1272. doi: 10.4161/auto.20872 22669536

43. Backues SK, Orban DP, Bernard A, Singh K, Cao Y, et al. (2015) Atg23 and Atg27 act at the early stages of Atg9 trafficking in S. cerevisiae. Traffic 16: 172–190. doi: 10.1111/tra.12240 25385507

44. Gardner BM, Pincus D, Gotthardt K, Gallagher CM, Walter P (2013) Endoplasmic reticulum stress sensing in the unfolded protein response. Cold Spring Harbor perspectives in biology 5: a013169. doi: 10.1101/cshperspect.a013169 23388626

45. Ron D, Walter P (2007) Signal integration in the endoplasmic reticulum unfolded protein response. Nature reviews Molecular cell biology 8: 519–529. 17565364

46. Carvalho P, Goder V, Rapoport TA (2006) Distinct ubiquitin-ligase complexes define convergent pathways for the degradation of ER proteins. Cell 126: 361–373. 16873066

47. Graef M, Friedman JR, Graham C, Babu M, Nunnari J (2013) ER exit sites are physical and functional core autophagosome biogenesis components. Molecular biology of the cell 24: 2918–2931. doi: 10.1091/mbc.E13-07-0381 23904270

48. McCusker EC, Bane SE, O'Malley MA, Robinson AS (2007) Heterologous GPCR expression: a bottleneck to obtaining crystal structures. Biotechnology progress 23: 540–547. 17397185

49. Corrigan PA, Cicci TA, Auten JJ, Lowe DK (2014) Ado-trastuzumab emtansine: a HER2-positive targeted antibody-drug conjugate. The Annals of pharmacotherapy 48: 1484–1493. doi: 10.1177/1060028014545354 25082874

50. Eroglu Z, Tagawa T, Somlo G (2014) Human epidermal growth factor receptor family-targeted therapies in the treatment of HER2-overexpressing breast cancer. The oncologist 19: 135–150. doi: 10.1634/theoncologist.2013-0283 24436312

51. Caffarel MM, Coleman N (2014) Oncostatin M receptor is a novel therapeutic target in cervical squamous cell carcinoma. The Journal of pathology 232: 386–390. doi: 10.1002/path.4305 24659184

52. Gunel C, Feldman RE, Bleier BS (2014) Osteitis is associated with P-glycoprotein overexpression in patients with chronic sinusitis without nasal polyps. American journal of rhinology & allergy 28: 99–102.

53. Matus S, Lisbona F, Torres M, Leon C, Thielen P, et al. (2008) The stress rheostat: an interplay between the unfolded protein response (UPR) and autophagy in neurodegeneration. Current molecular medicine 8: 157–172. 18473817

54. Mochida K, Oikawa Y, Kimura Y, Kirisako H, Hirano H, et al. (2015) Receptor-mediated selective autophagy degrades the endoplasmic reticulum and the nucleus. Nature 522: 359–362. doi: 10.1038/nature14506 26040717

55. Khaminets A, Heinrich T, Mari M, Grumati P, Huebner AK, et al. (2015) Regulation of endoplasmic reticulum turnover by selective autophagy. Nature 522: 354–358. doi: 10.1038/nature14498 26040720

56. Parrish ML, Sengstag C, Rine JD, Wright RL (1995) Identification of the sequences in HMG-CoA reductase required for karmellae assembly. Molecular biology of the cell 6: 1535–1547. 8589454

57. Beh CT, Rose MD (1995) Two redundant systems maintain levels of resident proteins within the yeast endoplasmic reticulum. Proceedings of the National Academy of Sciences of the United States of America 92: 9820–9823. 7568225

58. Vida TA, Emr SD (1995) A new vital stain for visualizing vacuolar membrane dynamics and endocytosis in yeast. The Journal of cell biology 128: 779–792. 7533169

59. Nishikawa S, Hirata A, Nakano A (1994) Inhibition of endoplasmic reticulum (ER)-to-Golgi transport induces relocalization of binding protein (BiP) within the ER to form the BiP bodies. Molecular biology of the cell 5: 1129–1143. 7865879

60. Kruse KB, Brodsky JL, McCracken AA (2006) Characterization of an ERAD gene as VPS30/ATG6 reveals two alternative and functionally distinct protein quality control pathways: one for soluble Z variant of human alpha-1 proteinase inhibitor (A1PiZ) and another for aggregates of A1PiZ. Molecular biology of the cell 17: 203–212. 16267277

61. Reynolds A, Lundblad V, Dorris D, Keaveney M (2001) Yeast vectors and assays for expression of cloned genes. Current protocols in molecular biology / edited by Frederick M Ausubel [et al] Chapter 13: Unit13 16.

Štítky
Genetika Reprodukčná medicína

Článok vyšiel v časopise

PLOS Genetics


2015 Číslo 7
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Získaná hemofilie - Povědomí o nemoci a její diagnostika
nový kurz

Eozinofilní granulomatóza s polyangiitidou
Autori: doc. MUDr. Martina Doubková, Ph.D.

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa

#ADS_BOTTOM_SCRIPTS#