UBAC2 phosphorylation is essential for its role in ER-phagy

ER-phagy, a selective degradation of endoplasmic reticulum (ER) fragment, plays a critical role in maintaining the ER homeostasis. Dysregulation of ER-phagy is involved in the unfolded protein response (UPR), which serves as a vital clue to evoke inflammatory disease. 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 bind 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 ER-phagy directed by MARK2-UBAC2 axis can provide therapy target for inflammatory disease.