Individual Atg8 paralogs and a bacterial metabolite sequentially promote hierarchical CASM-xenophagy induction and transition

Chisato Sakuma; Sayaka Shizukuishi; Michinaga Ogawa; Yuko Honjo; Haruko Takeyama; Jun-Lin Guan; Jeffery Weiser; Miwa Sasai; Masahiro Yamamoto; Makoto Ohnishi; Yukihiro Akeda

doi:10.1016/j.celrep.2024.114131

Individual Atg8 paralogs and a bacterial metabolite sequentially promote hierarchical CASM-xenophagy induction and transition

Cell Rep. 2024 Apr 23;43(5):114131. doi: 10.1016/j.celrep.2024.114131. Online ahead of print.

Authors

Affiliations

¹ Department of Bacteriology I, National Institute of Infectious Diseases, 1-23-1, Toyama, Shinjuku-ku, Tokyo 162-8640, Japan.
² Department of Bacteriology I, National Institute of Infectious Diseases, 1-23-1, Toyama, Shinjuku-ku, Tokyo 162-8640, Japan. Electronic address: micogawa@niid.go.jp.
³ Department of Bacteriology I, National Institute of Infectious Diseases, 1-23-1, Toyama, Shinjuku-ku, Tokyo 162-8640, Japan; Department of Life Science and Medical Bioscience, Waseda University, 2-2 Wakamatsu-cho, Shinjuku-ku, Tokyo 162-8480, Japan.
⁴ Department of Life Science and Medical Bioscience, Waseda University, 2-2 Wakamatsu-cho, Shinjuku-ku, Tokyo 162-8480, Japan; Computational Bio Big-Data Open Innovation Laboratory, AIST-Waseda University, 3-4-1 Okubo, Shinjuku-ku, Tokyo 169-0072, Japan; Research Organization for Nano & Life Innovation, Waseda University, 513 Wasedatsurumaki-cho, Shinjuku-ku, Tokyo 162-0041, Japan; Institute for Advanced Research of Biosystem Dynamics, Waseda Research Institute for Science and Engineering, Waseda University, 3-4-1 Okubo, Shinjuku-ku, Tokyo, 169-8555, Japan.
⁵ Department of Cancer Biology, University of Cincinnati College of Medicine, CARE/Crawley Building, Suite E-870 3230 Eden Avenue, Cincinnati, OH 45267, USA.
⁶ Department of Microbiology, NYU Grossman School of Medicine, New York, NY 10016, USA.
⁷ Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan; Laboratory of Immunoparasitology, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan; Department of Immunoparasitology, Center for Infectious Disease Education and Research, Osaka University, Suita, Osaka 565-0871, Japan.

PMID: 38656870
DOI: 10.1016/j.celrep.2024.114131

Abstract

Atg8 paralogs, consisting of LC3A/B/C and GBRP/GBRPL1/GATE16, function in canonical autophagy; however, their function is controversial because of functional redundancy. In innate immunity, xenophagy and non-canonical single membranous autophagy called "conjugation of Atg8s to single membranes" (CASM) eliminate bacteria in various cells. Previously, we reported that intracellular Streptococcus pneumoniae can induce unique hierarchical autophagy comprised of CASM induction, shedding, and subsequent xenophagy. However, the molecular mechanisms underlying these processes and the biological significance of transient CASM induction remain unknown. Herein, we profile the relationship between Atg8s, autophagy receptors, poly-ubiquitin, and Atg4 paralogs during pneumococcal infection to understand the driving principles of hierarchical autophagy and find that GATE16 and GBRP sequentially play a pivotal role in CASM shedding and subsequent xenophagy induction, respectively, and LC3A and GBRPL1 are involved in CASM/xenophagy induction. Moreover, we reveal ingenious bacterial tactics to gain intracellular survival niches by manipulating CASM-xenophagy progression by generating intracellular pneumococci-derived H₂O₂.

Keywords: Atg4s; Atg8s; CASM; CP: Cell biology; CP: Microbiology; Streptococcus pneumoniae; autophagy matrix profiling; hierarchical autophagy; pneumococci-derived H(2)O(2); poly-ubiquitin; xenophagy.