5cqc

Structural highlights

Function

RAVZ_LEGPH Cysteine protease effector that inhibits host cell autophagy by targeting lipid-conjugated ATG8 family proteins on pre-autophagosomal structures (PubMed:23112293, PubMed:29458288, PubMed:32686895, PubMed:31722778, PubMed:31719622, PubMed:33298241, PubMed:26343456, PubMed:28395732). Specifically hydrolyzes the amide bond between the C-terminal glycine residue and an adjacent aromatic residue in ATG8 proteins conjugated to phosphatidylethanolamine (PE), producing an ATG8 protein that cannot be reconjugated by host ATG7 and ATG3 (PubMed:23112293, PubMed:29458288, PubMed:32686895, PubMed:26343456, PubMed:28395732). Mechanistically, Ravz interacts with ATG8 proteins conjugated to PE via its LIR motifs, extracts them from the membrane of autophagosomes and integrates the PE part into its own lipid-binding site (PubMed:28395732). It then removes the lipid component of the ATG8 protein (PubMed:28395732). Also able to mediate delipidation of ATG8 proteins conjugated to phosphatidylserine (PS) during non-canonical autophagy (PubMed:33909989). Inhibits host ubiquitin recruitment to bacteria-containing vacuoles, suggesting that it is able to mediate delipidation of other proteins in addition to ATG8 proteins (PubMed:28971069). It is however not involved in the exclusion of autophagy adapters from bacteria-containing vacuoles decorated with ubiquitin (PubMed:32482642).^{[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11]}

References

1. ↑ Choy A, Dancourt J, Mugo B, O'Connor TJ, Isberg RR, Melia TJ, Roy CR. The Legionella effector RavZ inhibits host autophagy through irreversible Atg8 deconjugation. Science. 2012 Nov 23;338(6110):1072-6. PMID:23112293 doi:10.1126/science.1227026
2. ↑ Horenkamp FA, Kauffman KJ, Kohler LJ, Sherwood RK, Krueger KP, Shteyn V, Roy CR, Melia TJ, Reinisch KM. The Legionella Anti-autophagy Effector RavZ Targets the Autophagosome via PI3P- and Curvature-Sensing Motifs. Dev Cell. 2015 Sep 14;34(5):569-76. doi: 10.1016/j.devcel.2015.08.010. Epub 2015 , Sep 3. PMID:26343456 doi:http://dx.doi.org/10.1016/j.devcel.2015.08.010
3. ↑ Yang A, Pantoom S, Wu YW. Elucidation of the anti-autophagy mechanism of the Legionella effector RavZ using semisynthetic LC3 proteins. Elife. 2017 Apr 11;6. pii: e23905. doi: 10.7554/eLife.23905. PMID:28395732 doi:http://dx.doi.org/10.7554/eLife.23905
4. ↑ Kubori T, Bui XT, Hubber A, Nagai H. Legionella RavZ Plays a Role in Preventing Ubiquitin Recruitment to Bacteria-Containing Vacuoles. Front Cell Infect Microbiol. 2017 Aug 28;7:384. PMID:28971069 doi:10.3389/fcimb.2017.00384
5. ↑ Kauffman KJ, Yu S, Jin J, Mugo B, Nguyen N, O'Brien A, Nag S, Lystad AH, Melia TJ. Delipidation of mammalian Atg8-family proteins by each of the four ATG4 proteases. Autophagy. 2018;14(6):992-1010. PMID:29458288 doi:10.1080/15548627.2018.1437341
6. ↑ Park SW, Jeon P, Jun YW, Park JH, Lee SH, Lee S, Lee JA, Jang DJ. Monitoring LC3 RavZ-based probes. Sci Rep. 2019 Nov 12;9(1):16593. PMID:31719622 doi:10.1038/s41598-019-53372-2
7. ↑ Park SW, Jun YW, Jeon P, Lee YK, Park JH, Lee SH, Lee JA, Jang DJ. LIR motifs and the membrane-targeting domain are complementary in the function of RavZ. BMB Rep. 2019 Dec;52(12):700-705. PMID:31722778 doi:10.5483/BMBRep.2019.52.12.211
8. ↑ Omotade TO, Roy CR. Legionella pneumophila Excludes Autophagy Adaptors from the Ubiquitin-Labeled Vacuole in Which It Resides. Infect Immun. 2020 Jul 21;88(8):e00793-19. PMID:32482642 doi:10.1128/IAI.00793-19
9. ↑ Yang A, Pantoom S, Wu YW. Distinct Mechanisms for Processing Autophagy Protein LC3-PE by RavZ and ATG4B. Chembiochem. 2020 Dec 1;21(23):3377-3382. PMID:32686895 doi:10.1002/cbic.202000359
10. ↑ Park JH, Lee SH, Park SW, Jun YW, Kim K, Jeon P, Kim M, Lee JA, Jang DJ. Deciphering the role of a membrane-targeting domain in assisting endosomal and autophagic membrane localization of a RavZ protein catalytic domain. BMB Rep. 2021 Feb;54(2):118-123. PMID:33298241 doi:10.5483/BMBRep.2021.54.2.190
11. ↑ Durgan J, Lystad AH, Sloan K, Carlsson SR, Wilson MI, Marcassa E, Ulferts R, Webster J, Lopez-Clavijo AF, Wakelam MJ, Beale R, Simonsen A, Oxley D, Florey O. Non-canonical autophagy drives alternative ATG8 conjugation to phosphatidylserine. Mol Cell. 2021 May 6;81(9):2031-2040.e8. PMID:33909989 doi:10.1016/j.molcel.2021.03.020