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ER-phagy restrains inflammatory responses through its receptor UBAC2

ABSTRACT: ER-phagy, a selective form of autophagic degradation of endoplasmic reticulum (ER) fragment, plays an essential role in governing the ER homeostasis. Dysregulation of ER-phagy is associated with the unfolded protein response (UPR), which serves as a vital clue to evoke 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 an ER-phagy receptor, but a negative regulator of inflammatory responses. UBAC2 harbors a canonical LC3-interacting region (LIR) in the cytoplasmic domain that binds to autophagosomal GABARAP. Upon ER-stress or autophagy activation condition, microtubule affinity-regulating kinase 2 (MARK2) catalyzes the phosphorylation of UBAC2 at serine (S) 223 to promote its dimerization. Dimerized UBAC2 exhibits a stronger ability to interact with GABARAP for selective degradation of ER. Moreover, UBAC2 restrains inflammatory responses and acute ulcerative colitis (UC) in mice through affecting the ER-phagy. Our findings reveal that ER-phagy directed by MARK2-UBAC2 axis can provide therapy targets for inflammatory diseases.

ORGANISM(S): Homo sapiens (human) Mus musculus (mouse)

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PROVIDER: S-BSST1434 | biostudies-other |

SECONDARY ACCESSION(S): https

REPOSITORIES: biostudies-other

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