Abstract
Viral infection activates several transcription factors including NF-κB and IRF3, which collaborate to induce type I interferons (IFNs) and innate antiviral response. MITA (also called STING) is a critical adaptor protein that links virus-sensing receptors to IRF3 activation upon infection by both RNA and DNA pathogens. Here we show that the E3 ubiquitin ligase tripartite motif protein 32 (TRIM32) ubiquitinated MITA and dramatically enhanced MITA-mediated induction of IFN-β. Overexpression of TRIM32 potentiated virus-triggered IFNB1 expression and cellular antiviral response. Consistently, knockdown of TRIM32 had opposite effects. TRIM32 interacted with MITA, and was located at the mitochondria and endoplasmic reticulum. TRIM32 targeted MITA for K63-linked ubiquitination at K20/150/224/236 through its E3 ubiquitin ligase activity, which promoted the interaction of MITA with TBK1. These findings suggest that TRIM32 is an important regulatory protein for innate immunity against both RNA and DNA viruses by targeting MITA for K63-linked ubiquitination and downstream activation.
Highlights
MITA is an adapter protein critically involved in virus-triggered type I IFN induction and cellular antiviral response
Modulation of MITA Ubiquitination and Function by tripartite motif protein 32 (TRIM32)—Ubiquitination has emerged as a critical post-translational regulatory mechanism for virus-triggered type I IFN induction pathways
To determine whether TRIM32 plays a role in virus-induced expression of downstream genes, we examined its effects on Sendai virus (SeV, a negative-sense RNA virus)- and Herpes Simplex Virus 1 (HSV-1, a DNA virus)-triggered transcription of TNF␣ and IFNB1 genes
Summary
MITA is an adapter protein critically involved in virus-triggered type I IFN induction and cellular antiviral response. MITA, known as STING/ERIS/MPYS, has been identified as a mitochondrion- and ER-associated membrane protein that is critically involved in type I IFN induction and antiviral innate immunity in responding to both RNA and DNA virus infection under certain circumstances (16 –20). MEFs lacking MITA are defective in VSVand SeV-triggered type I IFN production or STAT6-mediated induction of a set of chemokines, suggesting that MITA plays an pivotal role in antiviral innate immune response to RNA viruses (16 –18, 21). It has been demonstrated that MITA acts as a direct sensor of cyclic dinucleotides which is known as a pathogen-secreted second messenger [22] These studies together reveal a critical role for MITA in innate immunity triggered by cytosolic viral or microbial nucleic acids. Our findings suggest that TRIM32-mediated K63-linked ubiquitination of MITA is an important step in virus-triggered IFN induction and cellular antiviral innate immunity
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