Wikipedia

Atg8ylation

(Redirected from Draft:Atg8ylation)

Atg8ylation is a process of conjugation of mammalian ATG8 proteins (mATG8s) to proteins or membranes.[1] The process is akin to the ubiquitylation of diverse substrates by ubiquitin.  There are six principal mATG8s: LC3A, LC3B, LC3C, GABARAP, GABARAPL1 and GABARAPL2.[2] Together, they comprise a sub-class of ubiquitin-like molecules characterized by two N-terminal α-helices added to the ubiquitin core, which serve a dual role of forming a docking site for interacting proteins containing ATG8-interaction motifs and enhancing mATG8’s affinity for membranes.[3]

Membrane atg8ylation

edit
 
Membrane atg8ylation and its biological outputs in mammalian cells.

Membrane atg8ylation is a response to membrane stress, damage, and remodeling inputs.[1] This process is best appreciated by analogy to ubiquitylation considering that atg8ylation is to membranes what ubiquitylation is to proteins.[1] Membrane atg8ylation occurs via covalent modification by mATG8s of the membrane phospholipids phosphatidylethanolamine and phosphatidylserine.[4] The conjugation cascade that activates mATG8s and results in membrane atg8ylation is biochemically similar to protein ubiquitylation, as both systems require ATP, E1, E2 and E3 ligases.[4] The specific factors leading to atg8ylation include two enzymatic cascades with ATG12-ATG5 and mATG8-phosphatidylethanolamine (PE) conjugates as their end products.[4] The ATG12-ATG5 protein-protein conjugate combines with additional proteins such as ATG16L1 or TECPR1 to form E3 ligases that spatially guide the formation of protein-lipid conjugate resulting in atg8ylation of specific membrane domains[5]

The specialization of atg8ylation for membranes is ensured by the two extra (relative to ubiquitin) α-helices at the N-terminus of mATG8s with concealed affinities for membranes realized during atg8ylation and intrinsic membrane affinities of the atg8ylation cascade E2 component ATG3, as well as E3 components ATG16L1 or TECPR.[3]

Principles of membrane atg8ylation

edit

Mammalian membranes that undergo atg8ylation include: canonical autophagosomes, phagosomes harboring phagocytosed pathogens or microbial products, perturbed or signaling endosomes, damaged lysosomes, exocytic compartments releasing exosomes, endoplasmic reticulum (ER) during its piecemeal ESCRT-dependent lysosomal degradation, and lipid droplets.[6] The delimiting membrane of lipid droplets modified by LC3B is not a full lipid bilayer but a monolayer of phospholipids surrounding neutral lipid core.[7] The lipid droplet atg8ylation illustrates the principle that any cellular membrane may undergo atg8ylation including double membranes of autophagosomes (double lipid bilayer), single membranes (single lipid bilayer) of phagosomes and endosomes, and a phospholipid monolayer (hemilayer) surrounding lipid droplets.  

During canonical autophagy, which includes atg8ylation of growing phagophores, WIPI2, an effector of phosphatidylinositol-3-phosphate (a stress-signaling phosphoinositide phospholipid) and a known interactor of ATG16L1 , helps dock the E3 ligase ATG12-ATG5/ATG16L1 to the phosphatidylinositol-3-phosphate-marked membranes.[8] This presents activated mATG8s for conjugation to the phospholipid phosphatidylethanolamine embedded within the target membrane.[9]

During noncanonical atg8ylation of stressed, damaged or remodeling membranes other than autophagosomes, the E3 ligases are recruited to target membranes by a variety of mechanisms. This includes docking of the ATG12-ATG5/ATG16L1 E3 ligase on vacuolar compartments including phagosomes, endosomes and lysosomes via binding of ATG16L1 to the vacuolar-type ATPase (v-ATPase).[10] This binding is stimulated when the lumenal pH of the vacuole is perturbed.[11] In other instances, the ATG12-ATG5/TECPR1 E3 ligase docks to stressed membranes via TECPR1, which recognizes the citofacially displayed sphingomyelin misplaced and exposed on perturbed membranes.[12]

Manifestations of membrane atg8ylation

edit

Atg8ylation is an important aspect of canonical autophagy.[1]  The initial stages of autophagy morphologically detectable as crescent phagophores do occur independently of all principal mATG8s.[13] Phagophore formation proceeds in cells defective for mATG8 lipidation.[14] However, the size of autophagosomes is smaller without atg8ylation.[13] Further, the quality of autophagosomal membranes, such as membrane permeability, are adversely affected.[15] The known effects of atg8ylation on autophagosomal membranes include membrane remodeling, kinetic effects, selective cargo sequestration into autophagosomes, and effects on autophagosome-lysosome fusion.[16] Atg8ylation is important for ESCRT-dependent sealing of nascent autophagosomes and for their maintenance in an impervious state.[15]

The non-autophagic processes dependent on atg8ylation include: LAP (LC3-associated phagocytosis), LANDO (LC3-associated endocytosis), LC3-associated micropinocytosis (LAM), CASM (conjugation of ATG8 to single membranes) alternatively referred to as SMAC (single membrane ATG8 conjugation) , and ‘vATPase-ATG16L1 axis xenophagy’ known under an acronym VAIL (V-ATPase-ATG16L1-induced LC3 lipidation).[1][17]   Many of the physiological and disease-associated effects of atg8ylation are manifested via these noncanonical processes or through canonical autophagy.[18][19]

References

edit
  1. ^ a b c d e Deretic, Vojo; Lazarou, Michael (2022-07-04). "A guide to membrane atg8ylation and autophagy with reflections on immunity". The Journal of Cell Biology. 221 (7): e202203083. doi:10.1083/jcb.202203083. ISSN 1540-8140. PMC 9202678. PMID 35699692.
  2. ^ Weidberg, Hilla; Shvets, Elena; Shpilka, Tomer; Shimron, Frida; Shinder, Vera; Elazar, Zvulun (2010-06-02). "LC3 and GATE-16/GABARAP subfamilies are both essential yet act differently in autophagosome biogenesis". The EMBO Journal. 29 (11): 1792–1802. doi:10.1038/emboj.2010.74. ISSN 1460-2075. PMC 2885923. PMID 20418806.
  3. ^ a b Zhang, Wenxin; Nishimura, Taki; Gahlot, Deepanshi; Saito, Chieko; Davis, Colin; Jefferies, Harold B. J.; Schreiber, Anne; Thukral, Lipi; Tooze, Sharon A. (2023-06-08). "Autophagosome membrane expansion is mediated by the N-terminus and cis-membrane association of human ATG8s". eLife. 12: e89185. doi:10.7554/eLife.89185. ISSN 2050-084X. PMC 10289813. PMID 37288820.
  4. ^ a b c Mizushima, Noboru (April 2020). "The ATG conjugation systems in autophagy". Current Opinion in Cell Biology. 63: 1–10. doi:10.1016/j.ceb.2019.12.001. ISSN 1879-0410. PMID 31901645. S2CID 209895364.
  5. ^ Kaur, Namrita; de la Ballina, Laura Rodriguez; Haukaas, Håvard Styrkestad; Torgersen, Maria Lyngaas; Radulovic, Maja; Munson, Michael J.; Sabirsh, Alan; Stenmark, Harald; Simonsen, Anne; Carlsson, Sven R.; Lystad, Alf Håkon (2023-09-04). "TECPR1 is activated by damage-induced sphingomyelin exposure to mediate noncanonical autophagy". The EMBO Journal. 42 (17): e113105. doi:10.15252/embj.2022113105. ISSN 1460-2075. PMC 10476171. PMID 37409525.
  6. ^ Deretic, Vojo; Klionsky, Daniel J. (2024-01-15). "An expanding repertoire of E3 ligases in membrane Atg8ylation". Nature Cell Biology. 26 (3): 307–308. doi:10.1038/s41556-023-01329-z. ISSN 1476-4679. PMC 11164235. PMID 38225349. S2CID 266998336.
  7. ^ Omrane, Mohyeddine; Ben M'Barek, Kalthoum; Santinho, Alexandre; Nguyen, Nathan; Nag, Shanta; Melia, Thomas J.; Thiam, Abdou Rachid (2023-07-24). "LC3B is lipidated to large lipid droplets during prolonged starvation for noncanonical autophagy". Developmental Cell. 58 (14): 1266–1281.e7. doi:10.1016/j.devcel.2023.05.009. ISSN 1878-1551. PMC 10686041. PMID 37315562. S2CID 259162320.
  8. ^ Dooley, Hannah C.; Razi, Minoo; Polson, Hannah E. J.; Girardin, Stephen E.; Wilson, Michael I.; Tooze, Sharon A. (2014-07-17). "WIPI2 links LC3 conjugation with PI3P, autophagosome formation, and pathogen clearance by recruiting Atg12-5-16L1". Molecular Cell. 55 (2): 238–252. doi:10.1016/j.molcel.2014.05.021. ISSN 1097-4164. PMC 4104028. PMID 24954904.
  9. ^ Rao, Shanlin; Strong, Lisa M.; Ren, Xuefeng; Skulsuppaisarn, Marvin; Lazarou, Michael; Hurley, James H.; Hummer, Gerhard (2023-07-17). Three-step docking by WIPI2, ATG16L1 and ATG3 delivers LC3 to the phagophore (Report). Cell Biology. doi:10.1101/2023.07.17.549391.
  10. ^ Xu, Yue; Zhou, Ping; Cheng, Sen; Lu, Qiuhe; Nowak, Kathrin; Hopp, Ann-Katrin; Li, Lin; Shi, Xuyan; Zhou, Zhiwei; Gao, Wenqing; Li, Da; He, Huabin; Liu, Xiaoyun; Ding, Jingjin; Hottiger, Michael O. (2019-07-25). "A Bacterial Effector Reveals the V-ATPase-ATG16L1 Axis that Initiates Xenophagy". Cell. 178 (3): 552–566.e20. doi:10.1016/j.cell.2019.06.007. ISSN 1097-4172. PMID 31327526. S2CID 197466539.
  11. ^ Goodwin, Jonathan M.; Walkup, Ward G.; Hooper, Kirsty; Li, Taoyingnan; Kishi-Itakura, Chieko; Ng, Aylwin; Lehmberg, Timothy; Jha, Archana; Kommineni, Sravya; Fletcher, Katherine; Garcia-Fortanet, Jorge; Fan, Yaya; Tang, Qing; Wei, Menghao; Agrawal, Asmita (October 2021). "GABARAP sequesters the FLCN-FNIP tumor suppressor complex to couple autophagy with lysosomal biogenesis". Science Advances. 7 (40): eabj2485. Bibcode:2021SciA....7.2485G. doi:10.1126/sciadv.abj2485. ISSN 2375-2548. PMC 10938568. PMID 34597140. S2CID 238249006.
  12. ^ Boyle, Keith B.; Ellison, Cara J.; Elliott, Paul R.; Schuschnig, Martina; Grimes, Krista; Dionne, Marc S.; Sasakawa, Chihiro; Munro, Sean; Martens, Sascha; Randow, Felix (2023-09-04). "TECPR1 conjugates LC3 to damaged endomembranes upon detection of sphingomyelin exposure". The EMBO Journal. 42 (17): e113012. doi:10.15252/embj.2022113012. ISSN 1460-2075. PMC 10476172. PMID 37409490.
  13. ^ a b Nguyen, Thanh Ngoc; Padman, Benjamin Scott; Usher, Joanne; Oorschot, Viola; Ramm, Georg; Lazarou, Michael (2016-12-19). "Atg8 family LC3/GABARAP proteins are crucial for autophagosome-lysosome fusion but not autophagosome formation during PINK1/Parkin mitophagy and starvation". The Journal of Cell Biology. 215 (6): 857–874. doi:10.1083/jcb.201607039. ISSN 1540-8140. PMC 5166504. PMID 27864321.
  14. ^ Tsuboyama, Kotaro; Koyama-Honda, Ikuko; Sakamaki, Yuriko; Koike, Masato; Morishita, Hideaki; Mizushima, Noboru (2016-11-25). "The ATG conjugation systems are important for degradation of the inner autophagosomal membrane". Science. 354 (6315): 1036–1041. Bibcode:2016Sci...354.1036T. doi:10.1126/science.aaf6136. ISSN 1095-9203. PMID 27885029. S2CID 39627761.
  15. ^ a b Javed, Ruheena; Jain, Ashish; Duque, Thabata; Hendrix, Emily; Paddar, Masroor Ahmad; Khan, Sajjad; Claude-Taupin, Aurore; Jia, Jingyue; Allers, Lee; Wang, Fulong; Mudd, Michal; Timmins, Graham; Lidke, Keith; Rusten, Tor Erik; Akepati, Prithvi Reddy (2023-07-17). "Mammalian ATG8 proteins maintain autophagosomal membrane integrity through ESCRTs". The EMBO Journal. 42 (14): e112845. doi:10.15252/embj.2022112845. ISSN 1460-2075. PMC 10350836. PMID 37272163.
  16. ^ Rogov, Vladimir V.; Nezis, Ioannis P.; Tsapras, Panagiotis; Zhang, Hong; Dagdas, Yasin; Noda, Nobuo N.; Nakatogawa, Hitoshi; Wirth, Martina; Mouilleron, Stephane; McEwan, David G.; Behrends, Christian; Deretic, Vojo; Elazar, Zvulun; Tooze, Sharon A.; Dikic, Ivan (2023-12-31). "Atg8 family proteins, LIR/AIM motifs and other interaction modes". Autophagy Reports. 2 (1). doi:10.1080/27694127.2023.2188523. ISSN 2769-4127. PMC 7615515. PMID 38214012.
  17. ^ Galluzzi, Lorenzo; Green, Douglas R. (2019-06-13). "Autophagy-Independent Functions of the Autophagy Machinery". Cell. 177 (7): 1682–1699. doi:10.1016/j.cell.2019.05.026. ISSN 1097-4172. PMC 7173070. PMID 31199916.
  18. ^ Deretic, Vojo (2021-03-09). "Autophagy in inflammation, infection, and immunometabolism". Immunity. 54 (3): 437–453. doi:10.1016/j.immuni.2021.01.018. ISSN 1097-4180. PMC 8026106. PMID 33691134.
  19. ^ Klionsky, Daniel J.; Petroni, Giulia; Amaravadi, Ravi K.; Baehrecke, Eric H.; Ballabio, Andrea; Boya, Patricia; Bravo-San Pedro, José Manuel; Cadwell, Ken; Cecconi, Francesco; Choi, Augustine M. K.; Choi, Mary E.; Chu, Charleen T.; Codogno, Patrice; Colombo, Maria Isabel; Cuervo, Ana Maria (2021-10-01). "Autophagy in major human diseases". The EMBO Journal. 40 (19): e108863. doi:10.15252/embj.2021108863. ISSN 1460-2075. PMC 8488577. PMID 34459017.
Retrieved from "https://en.wikipedia.org/w/index.php?title=Atg8ylation&oldid=1243998483"