Degradation of p0071 and p120-catenin during adherens junction disassembly by Leptospira interrogans

Romina Tokumon; Isabel Sebastián; Bruno M Humbel; Nobuhiko Okura; Hidenori Yamanaka; Tetsu Yamashiro; Claudia Toma

doi:10.3389/fcimb.2023.1228051

Degradation of p0071 and p120-catenin during adherens junction disassembly by Leptospira interrogans

Front Cell Infect Microbiol. 2023 Sep 15:13:1228051. doi: 10.3389/fcimb.2023.1228051. eCollection 2023.

Authors

Romina Tokumon¹, Isabel Sebastián¹, Bruno M Humbel^{2

3

4}, Nobuhiko Okura⁵, Hidenori Yamanaka⁶, Tetsu Yamashiro¹, Claudia Toma¹

Affiliations

¹ Department of Bacteriology, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.
² Provost Office, Okinawa Institute of Science and Technology Graduate University, Okinawa, Japan.
³ Microscopy Center, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
⁴ Department of Cell Biology and Neuroscience, Juntendo University Graduate School of Medicine, Tokyo, Japan.
⁵ Department of Molecular Anatomy, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.
⁶ Environmental Technology Department, Chemicals Evaluation and Research Institute, Saitama, Japan.

Abstract

Leptospira interrogans disseminates hematogenously to reach the target organs by disrupting epithelial adherens junctions (AJs), thus causing leptospirosis, which is a globally neglected zoonotic disease. L. interrogans induces E-cadherin (E-cad) endocytosis and cytoskeletal rearrangement during AJ disassembly, but the detailed mechanism remains unknown. Elucidation of AJ disassembly mechanisms will guide new approaches to developing vaccines and diagnostic methods. In this study, we combine proteomic and imaging analysis with chemical inhibition studies to demonstrate that disrupting the AJs of renal proximal tubule epithelial cells involves the degradation of two armadillo repeat-containing proteins, p0071 and p120-catenin, that stabilize E-cad at the plasma membrane. Combining proteasomal and lysosomal inhibitors substantially prevented p120-catenin degradation, and monolayer integrity destruction without preventing p0071 proteolysis. In contrast, the pan-caspase inhibitor Z-VAD-FMK inhibited p0071 proteolysis and displacement of both armadillo repeat-containing proteins from the cell-cell junctions. Our results show that L. interrogans induces p120-catenin and p0071 degradation, which mutually regulates E-cad stability by co-opting multiple cellular degradation pathways. This strategy may allow L. interrogans to disassemble AJs and disseminate through the body efficiently.

Keywords: E-cadherin; Leptospira interrogans; adherens junction; epithelial cell; p0071; p120-catenin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adherens Junctions
Catenins / metabolism
Delta Catenin*
Leptospira interrogans* / metabolism
Proteomics

Substances

Delta Catenin
Catenins

Grants and funding

This work was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI 21H02732 and the Takeda Science Foundation for the “High-Risk Emerging Infectious Diseases Research Grant” to CT. It was also partially supported by AMED “Research Support Project for Life Science and Drug Discovery (Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)) under Grant Number JP23ama121004 conferred to BH. Finally, the Program for Visiting Foreign Researchers at the University of the Ryukyus offers a salary to RT.