OTUD7B deubiquitinates SQSTM1/p62 and promotes IRF3 degradation to regulate antiviral immunity.

ABSTRACT

Deubiquitination plays an important role in the regulation of the crosstalk between macroautophagy/autophagy and innate immune signaling, yet its regulatory mechanisms are not fully understood. Here we identify the deubiquitinase OTUD7B as a negative regulator of antiviral immunity by targeting IRF3 (interferon regulatory factor 3) for selective autophagic degradation. Mechanistically, OTUD7B interacts with IRF3, and activates IRF3-associated cargo receptor SQSTM1/p62 (sequestosome 1) by removing its K63-linked poly-ubiquitin chains at lysine 7 (K7) to enhance SQSTM1 oligomerization. Moreover, viral infection increased the expression of OTUD7B, which forms a negative feedback loop by promoting IRF3 degradation to balance type I interferon (IFN) signaling. Taken together, our study reveals a specific role of OTUD7B in mediating the activation of cargo receptors in a substrate-dependent manner, which could be a potential target against excessive immune responses.Abbreviations Baf A1 bafilomycin A1; CGAS cyclic GMP-AMP synthase; DDX58/RIG-I DExD/H-box helicase 58; DSS dextran sodium sulfate; DUBs deubiquitinating enzymes; GFP green fluorescent protein; IFN interferon; IKKi IKBKB/IkappaB kinase inhibitor; IRF3 interferon regulatory factor 3; ISGs interferon-stimulated genes; MAVS mitochondrial antiviral signaling protein; MOI multiplicity of infection; PAMPs pathogen-associated molecular patterns; SeV Sendai virus; siRNA small interfering RNA; SQSTM1/p62 sequestosome 1; STING1 stimulator of interferon response cGAMP interactor 1; TBK1 TANK binding kinase 1; Ub ubiquitin; WT wild-type; VSV vesicular stomatitis virus.