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- Title
Opposing roles of RUBCN isoforms in autophagy and memory B cell generation.
- Authors
Tsai, Chao-Yuan; Sakakibara, Shuhei; Kuan, Yu-Diao; Omori, Hiroko; El Hussien, Maruwa Ali; Okuzaki, Daisuke; Lu, Shiou-Ling; Noda, Takeshi; Tabata, Keisuke; Nakamura, Shuhei; Yoshimori, Tamotsu; Kikutani, Hitoshi
- Abstract
RUBCN (also known as Rubicon) was originally identified as a negative regulator of autophagy, a process by which cells degrade and recycle damaged components or organelles and that requires the activity of the class III PI3K VPS34 and the mTORC1 protein complex. Here, we characterized the role of a shorter isoform, RUBCN100, as an autophagy-promoting factor in B cells. RUBCN100 was translated from alternative translation initiation sites and lacked the RUN domain of the longer, previously characterized RUBCN130 isoform. Specific deficiency of RUBCN130 in B cells enhanced autophagy, which promoted memory B cell generation. In contrast to RUBCN130, which is localized in late endosomes and lysosomes and suppresses the enzymatic activity of VPS34, an effect thought to mediated by its RUN domain, RUBCN100 was preferentially located in early endosomes and enhanced VPS34 activity, presumably because of the absence of the RUN domain. Furthermore, RUBCN100, but not RUBCN130, enhanced autophagy and suppressed mTORC1 activation. Our findings reveal that the opposing roles of two RUBCN isoforms are critical for autophagy regulation and memory B cell differentiation. Editor's summary: Memory B cells generated upon the first encounter with a pathogen persist to enable antibody-based defenses for subsequent encounters. The survival of memory B cells depends on autophagy, a process that eliminates damaged cellular components. The 130–amino acid protein Rubicon (RUBCN130) is thought to inhibit autophagy, and Tsai et al. characterized a shorter Rubicon isoform (RUBCN100) that enhanced autophagy in B cells. Mice with B cells that specifically lacked RUBCN130 generated more memory B cells in an autophagy-dependent manner. The differential effects on autophagy might be due to the ability of RUBCN130 to suppress the activity of autophagy-promoting proteins. The identification and characterization of the shorter Rubicon isoform help to resolve conflicting results regarding the function of Rubicon in autophagy. —Wei Wong
- Subjects
B cells; IMMUNOLOGIC memory; B cell differentiation; AUTOPHAGY; CELL anatomy; ENDOSOMES
- Publication
Science Signaling, 2023, Vol 16, Issue 803, p1
- ISSN
1945-0877
- Publication type
Article
- DOI
10.1126/scisignal.ade3599