2. Academic Validation
  3. ER-phagy restrains inflammatory responses through its receptor UBAC2

ER-phagy restrains inflammatory responses through its receptor UBAC2

  • EMBO J. 2024 Sep 16. doi: 10.1038/s44318-024-00232-z.
Xing He 1,  Haowei He 1,  Zitong Hou 1,  Zheyu Wang 1,  Qinglin Shi 1,  Tao Zhou 1,  Yaoxing Wu 2,  Yunfei Qin 3,  Jun Wang 4,  Zhe Cai 5,  Jun Cui 1,  Shouheng Jin 6
Affiliations

Affiliations

  • 1 Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
  • 2 Institute of Precision Medicine, Department of Critical Care Medicine, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • 3 Biotherapy Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • 4 Precision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 5 Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.
  • 6 Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China. jinshh3@mail.sysu.edu.cn.
PMID: 39284914 DOI: 10.1038/s44318-024-00232-z
Abstract

ER-phagy, a selective form of autophagic degradation of endoplasmic reticulum (ER) fragments, plays an essential role in governing ER homeostasis. Dysregulation of ER-phagy is associated with the unfolded protein response (UPR), which is a major clue for evoking inflammatory diseases. However, the molecular mechanism underpinning the connection between ER-phagy and disease remains poorly defined. Here, we identified ubiquitin-associated domain-containing protein 2 (UBAC2) as a receptor for ER-phagy, while at the same time being a negative regulator of inflammatory responses. UBAC2 harbors a canonical LC3-interacting region (LIR) in its cytoplasmic domain, which binds to autophagosomal GABARAP. Upon ER-stress or Autophagy activation, microtubule affinity-regulating kinase 2 (MARK2) phosphorylates UBAC2 at serine (S) 223, promoting its dimerization. Dimerized UBAC2 interacts more strongly with GABARAP, thus facilitating selective degradation of the ER. Moreover, by affecting ER-phagy, UBAC2 restrains inflammatory responses and acute ulcerative colitis (UC) in mice. Our findings indicate that ER-phagy directed by a MARK2-UBAC2 axis may provide targets for the treatment of inflammatory disease.

Keywords

Colitis; ER-phagy; Inflammatory Responses; MARK2; UBAC2.

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