TRIM14 Inhibits cGAS Degradation Mediated by Selective Autophagy Receptor p62 to Promote Innate Immune Responses

Abstract

Cyclic GMP-AMP synthase (cGAS) is an essential DNA virus sensor that triggers type I interferon (IFN) signaling by producing cGAMP to initiate antiviral immunity. However, post-translational regulation of cGAS remains largely unknown. We report that K48-linked ubiquitination of cGAS is a recognition signal for p62-depdendent selective autophagic degradation. The induction of TRIM14 by type I IFN accelerates cGAS stabilization by recruiting USP14 to cleave the ubiquitin chains of cGAS at lysine (K) 414. Knockout of TRIM14 impairs herpes simplex virus type 1 (HSV-1)-triggered antiviral responses in a cGAS-dependent manner. Due to impaired type I IFN production, Trim14 mice are highly susceptible to lethal HSV-1 infection. Taken together, our findings reveal a positive feedback loop of cGAS signaling generated by TRIM14-USP14 and provide insights into the crosstalk between autophagy and type I IFN signaling in innate immunity.

Meddling with Fate: The Proteasomal Deubiquitinating Enzymes

“…Loss of Ubp6 in yeast destabilizes several model and physiological proteasome substrates in vivo [45], and inhibition of the DUB activity of Usp14 in mammalian cells stimulates the degradation of specific proteasome substrates [41,102–108]. Accordingly, when Usp14 is activated by AKT, the degradation of multiple proteins appears to be suppressed [73].…”

“…Since the original study on IU1, several groups have reported proteins that show accelerated degradation under IU1 treatment, including the Prion protein PrP [102,103], cGAS [108], phosphorylated tyrosine hydroxylase [104], the androgen receptor [105], vimentin [106], aurora kinase [111], CREB-binding protein [75], YFP-tagged CD3δ [107], and the model UPS substrate GFP u [107]. In many of these studies, the on-target nature of the IU1 effect is supported by genetic confirmation [102,105–108].…”

“…In many of these studies, the on-target nature of the IU1 effect is supported by genetic confirmation [102,105–108]. For example, PrP is degraded more rapidly in the presence of IU1 or when Usp14 expression is reduced, and more slowly when Usp14 is overexpressed [102].…”

“…For example, PrP is degraded more rapidly in the presence of IU1 or when Usp14 expression is reduced, and more slowly when Usp14 is overexpressed [102]. Like PrP, cGAS, a key regulator of innate immunity, is an intriguing target [108]. In the absence of Usp14 activity, the ubiquitination of cGAS is elevated, which promotes its degradation not through the proteasome but through autophagy.…”

High Levels of TRIM14 Are Associated with Poor Prognosis in Hepatocellular Carcinoma

“…Recently, the involvement of TRIM14 in the host defense against viral infections was reported by 2 different groups. Chen et al [8] revealed that TRIM14 inhibited degradation of cyclic GMP-AMP synthase (cGAS) that was mediated by selective autophagy receptor p62 to promote innate immune responses during herpes simplex virus (HSV)-1 infection. Moreover, Wang et al [9] demonstrated that TRIM14 inhibited hepatitis C virus infection by SPRY domain-dependent targeted degradation of the viral NS5A protein.…”