Legionella Effectors SidC/SdcA Ubiquitinate Multiple Small GTPases and SNARE Proteins to Promote Phagosomal Maturation

Overview

Journal Cell Mol Life Sci

Publisher Springer

Specialty Biology

Date 2024 Jun 5

PMID 38836877

Authors

Kelong Ma

Rundong Shu

Hongtao Liu

Jinli Ge

Jiayang Liu

Qian Lu

Jiaqi Fu

Xiaoyun Liu

Jiazhang Qiu

Affiliations

Soon will be listed here.

Abstract

Protein ubiquitination is one of the most important posttranslational modifications (PTMs) in eukaryotes and is involved in the regulation of almost all cellular signaling pathways. The intracellular bacterial pathogen Legionella pneumophila translocates at least 26 effectors to hijack host ubiquitination signaling via distinct mechanisms. Among these effectors, SidC/SdcA are novel E3 ubiquitin ligases with the adoption of a Cys-His-Asp catalytic triad. SidC/SdcA are critical for the recruitment of endoplasmic reticulum (ER)-derived vesicles to the Legionella-containing vacuole (LCV). However, the ubiquitination targets of SidC/SdcA are largely unknown, which restricts our understanding of the mechanisms used by these effectors to hijack the vesicle trafficking pathway. Here, we demonstrated that multiple Rab small GTPases and target soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNARE) proteins are bona fide ubiquitination substrates of SidC/SdcA. SidC/SdcA-mediated ubiquitination of syntaxin 3 and syntaxin 4 promotes their unconventional pairing with the vesicle-SNARE protein Sec22b, thereby contributing to the membrane fusion of ER-derived vesicles with the phagosome. In addition, our data reveal that ubiquitination of Rab7 by SidC/SdcA is critical for its association with the LCV membrane. Rab7 ubiquitination could impair its binding with the downstream effector Rab-interacting lysosomal protein (RILP), which partially explains why LCVs avoid fusion with lysosomes despite the acquisition of Rab7. Taken together, our study reveals the biological mechanisms employed by SidC/SdcA to promote the maturation of the LCVs.

References

Rolando M, Wah Chung I, Xu C, Gomez-Valero L, England P, Cygler M . The SET and ankyrin domains of the secreted histone methyltransferase work together to modify host chromatin. mBio. 2023; 14(5):e0165523. PMC: 10653858. DOI: 10.1128/mbio.01655-23. View

Kitao T, Taguchi K, Seto S, Arasaki K, Ando H, Nagai H . Legionella Manipulates Non-canonical SNARE Pairing Using a Bacterial Deubiquitinase. Cell Rep. 2020; 32(10):108107. DOI: 10.1016/j.celrep.2020.108107. View

Kubori T, Arasaki K, Oide H, Kitao T, Nagai H . Multi-tiered actions of effectors to modulate host Rab10 dynamics. Elife. 2024; 12. PMC: 11108646. DOI: 10.7554/eLife.89002. View

Sun J, Deghmane A, Soualhine H, Hong T, Bucci C, Solodkin A . Mycobacterium bovis BCG disrupts the interaction of Rab7 with RILP contributing to inhibition of phagosome maturation. J Leukoc Biol. 2007; 82(6):1437-45. DOI: 10.1189/jlb.0507289. View

Cantalupo G, Alifano P, Roberti V, Bruni C, Bucci C . Rab-interacting lysosomal protein (RILP): the Rab7 effector required for transport to lysosomes. EMBO J. 2001; 20(4):683-93. PMC: 145419. DOI: 10.1093/emboj/20.4.683. View

Zheng N, Shabek N . Ubiquitin Ligases: Structure, Function, and Regulation. Annu Rev Biochem. 2017; 86:129-157. DOI: 10.1146/annurev-biochem-060815-014922. View

Tan Y, Arnold R, Luo Z . Legionella pneumophila regulates the small GTPase Rab1 activity by reversible phosphorylcholination. Proc Natl Acad Sci U S A. 2011; 108(52):21212-7. PMC: 3248503. DOI: 10.1073/pnas.1114023109. View

Hsu F, Luo X, Qiu J, Teng Y, Jin J, Smolka M . The Legionella effector SidC defines a unique family of ubiquitin ligases important for bacterial phagosomal remodeling. Proc Natl Acad Sci U S A. 2014; 111(29):10538-43. PMC: 4115505. DOI: 10.1073/pnas.1402605111. View

Liu S, Luo J, Zhen X, Qiu J, Ouyang S, Luo Z . Interplay between bacterial deubiquitinase and ubiquitin E3 ligase regulates ubiquitin dynamics on Legionella phagosomes. Elife. 2020; 9. PMC: 7669269. DOI: 10.7554/eLife.58114. View

10.

Rolando M, Sanulli S, Rusniok C, Gomez-Valero L, Bertholet C, Sahr T . Legionella pneumophila effector RomA uniquely modifies host chromatin to repress gene expression and promote intracellular bacterial replication. Cell Host Microbe. 2013; 13(4):395-405. DOI: 10.1016/j.chom.2013.03.004. View

11.

Berger K, Isberg R . Two distinct defects in intracellular growth complemented by a single genetic locus in Legionella pneumophila. Mol Microbiol. 1993; 7(1):7-19. DOI: 10.1111/j.1365-2958.1993.tb01092.x. View

12.

Wei C, Wang Y, Du Z, Guan K, Cao Y, Yang H . The Yersinia Type III secretion effector YopM Is an E3 ubiquitin ligase that induced necrotic cell death by targeting NLRP3. Cell Death Dis. 2016; 7(12):e2519. PMC: 5260993. DOI: 10.1038/cddis.2016.413. View

13.

Harrison R, Brumell J, Khandani A, Bucci C, Scott C, Jiang X . Salmonella impairs RILP recruitment to Rab7 during maturation of invasion vacuoles. Mol Biol Cell. 2004; 15(7):3146-54. PMC: 452572. DOI: 10.1091/mbc.e04-02-0092. View

14.

Ma K, Xian W, Liu H, Shu R, Ge J, Luo Z . Bacterial ubiquitin ligases hijack the host deubiquitinase OTUB1 to inhibit MTORC1 signaling and promote autophagy. Autophagy. 2024; 20(9):1968-1983. PMC: 11346569. DOI: 10.1080/15548627.2024.2353492. View

15.

Feng Y, Press B, Wandinger-Ness A . Rab 7: an important regulator of late endocytic membrane traffic. J Cell Biol. 1995; 131(6 Pt 1):1435-52. PMC: 2120682. DOI: 10.1083/jcb.131.6.1435. View

16.

Jeong M, Jeon H, Shin D . Ubiquitin-regulating effector proteins from Legionella. BMB Rep. 2022; 55(7):316-322. PMC: 9340081. View

17.

Shin D, Mukherjee R, Liu Y, Gonzalez A, Bonn F, Liu Y . Regulation of Phosphoribosyl-Linked Serine Ubiquitination by Deubiquitinases DupA and DupB. Mol Cell. 2019; 77(1):164-179.e6. PMC: 6941232. DOI: 10.1016/j.molcel.2019.10.019. View

18.

Bhuin T, Roy J . Rab proteins: the key regulators of intracellular vesicle transport. Exp Cell Res. 2014; 328(1):1-19. DOI: 10.1016/j.yexcr.2014.07.027. View

19.

Roy C, Berger K, Isberg R . Legionella pneumophila DotA protein is required for early phagosome trafficking decisions that occur within minutes of bacterial uptake. Mol Microbiol. 1998; 28(3):663-74. DOI: 10.1046/j.1365-2958.1998.00841.x. View

20.

Mukherjee S, Liu X, Arasaki K, McDonough J, Galan J, Roy C . Modulation of Rab GTPase function by a protein phosphocholine transferase. Nature. 2011; 477(7362):103-6. PMC: 3206611. DOI: 10.1038/nature10335. View