Work

Stub1 promotes chaperone-mediated autophagy to suppress antiviral immunity

Year: 2026

Type: article

Abstract: The E3 ubiquitin ligase Stub1 (CHIP) is a core regulator of protein homeostasis and antiviral innate immunity, with established roles in targeting RIG‑I and MAVS for proteasomal or autophagic degradation. Here, we summarize our recent work revealing that Stub1 negatively regulates type I interferon (IFN‑I) production by driving chaperone‑mediated autophagy (CMA)-dependent degradation of TBK1. Stub1 directly interacts with TBK1 and catalyzes K27‑linked polyubiquitination at lysine 344 (K344) of TBK1, which enables recognition by the CMA chaperone HSC70 via a conserved KFDKQ CMA recognition motif. Subsequently, ubiquitinated TBK1 is delivered to lysosomes via HSC70 and the lysosomal membrane protein LAMP2A for degradation. This process is independent of macroautophagy and the ubiquitin - proteasome system. Myeloid‑specific Stub1 knockout mice show enhanced IFN‑I responses, lower viral loads, and improved survival rates upon viral infection. This study defines a Stub1-CMA signaling axis that fine‑tunes antiviral immunity and expands the regulatory scope of ubiquitin codes in selective protein degradation pathways.

Source: Autophagy

DOI: 10.1080/15548627.2026.2667376

Authors: Hongyang Liu, Li Huang, Changjiang Weng

Institutions: Chinese Academy of Agricultural Sciences, Harbin Veterinary Research Institute

Language: English

Topic: interferon and immune responses

Subfield: Immunology

Field: Immunology and Microbiology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: green

Funder: National Natural Science Foundation of China