ER-phagy restrains inflammatory responses through its receptor UBAC2
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.
Authors
- Shouheng Jin (ORCID: https://orcid.org/0000-0002-2728-2859)
- Haowei He (ORCID: https://orcid.org/0000-0002-0358-4983)
- Jun Cui (ORCID: https://orcid.org/0000-0002-8000-3708)
- Zhe Cai (ORCID: https://orcid.org/0000-0001-9853-7380)
- Yunfei Qin (ORCID: https://orcid.org/0000-0002-4716-9714)
- Tao Zhou (ORCID: https://orcid.org/0000-0001-6222-2053)
- Yaoxing Wu (ORCID: https://orcid.org/0000-0002-3639-0202)
- Zheyu Wang (ORCID: https://orcid.org/0000-0002-8703-6334)
- Xing He (ORCID: https://orcid.org/0000-0002-7276-2165)
- Zitong Hou
- Qinglin Shi
- Jun Wang (ORCID: https://orcid.org/0000-0002-6278-0677)
Institutions
- Sun Yat-sen University (CN)
- Shanghai Jiao Tong University (CN)
- The First Affiliated Hospital, Sun Yat-sen University (CN)
- Shanghai First People's Hospital (CN)
- Third Affiliated Hospital of Sun Yat-sen University (CN)
- Shanghai Clinical Research Center (CN)
- Guangzhou Medical University (CN)
Publication Details
- Journal
- The EMBO Journal
- Published
- 2024-09-16
- DOI
- https://doi.org/10.1038/s44318-024-00232-z
- Citations
- 10
- Primary Topic
- Autophagy in Disease and Therapy
- Type
- article
- Field-Weighted Citation Impact
- 3.87
Funders
- National Natural Science Foundation of China
- Sun Yat-sen University
- Natural Science Foundation of Guangdong Province
- Fundamental Research Funds for the Central Universities
- Basic and Applied Basic Research Foundation of Guangdong Province