ER-phagy restrains inflammatory responses through its receptor UBAC2

Area of Science:

• Cell Biology
• Molecular Biology
• Immunology

Background:

• Endoplasmic reticulum homeostasis is crucial for cellular health.
• ER-phagy, a selective autophagic process, degrades ER fragments but its regulatory mechanisms and disease links are unclear.
• Dysregulation of ER-phagy is implicated in the unfolded protein response (UPR) and inflammatory diseases.

Purpose of the Study:

• To elucidate the molecular mechanisms connecting ER-phagy to inflammatory diseases.
• To identify novel receptors and regulators of ER-phagy.
• To investigate the role of identified factors in inflammatory conditions.

Main Methods:

• Identification of UBAC2 as an ER-phagy receptor.
• Characterization of UBAC2's interaction with GABARAP via its LIR domain.
• Analysis of MARK2-mediated phosphorylation and dimerization of UBAC2.
• Assessment of UBAC2's role in ER-phagy and inflammatory responses in mouse models of ulcerative colitis.

Main Results:

• UBAC2 was identified as a key receptor mediating ER-phagy.
• MARK2-dependent phosphorylation promotes UBAC2 dimerization and enhances its interaction with GABARAP, facilitating ER degradation.
• UBAC2 functions as a negative regulator of inflammatory responses.
• UBAC2 deficiency exacerbates acute ulcerative colitis in mice, indicating its protective role.

Conclusions:

• The MARK2-UBAC2 axis is a critical regulator of ER-phagy.
• UBAC2's dual role in promoting ER-phagy and suppressing inflammation suggests its therapeutic potential.
• Targeting the ER-phagy pathway via UBAC2 may offer novel strategies for treating inflammatory diseases like ulcerative colitis.