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Negative Regulation of MAVS-Mediated Innate Immune Response by PSMA7¹

Yongxia Jia^2,*, Ting Song^2,*, Congwen Wei^2,*, Caifei Ni^*, Zirui Zheng^*, Quanbin Xu^*, Hongfang Ma^*, Li Li^*, Yanhong Zhang^*, Xiang He, Yang Xu, Wei Shi^3, and Hui Zhong^3,*

^* State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing, China; Institute of Disease Control and Prevention, Beijing, China; and Key Laboratory for Molecular Enzymology and Engineering, Ji Lin University, Changchun, China

Innate immunity to viruses involves receptors such as Retinoic Acid Induced Gene-1 (RIG-I), which senses viral RNA and triggers a signaling pathway involving the outer mitochondrial membrane protein mitochondrial antiviral signaling (MAVS). Recent work has identified that NLRX1, a member of another class of innate immune receptors, sequesters MAVS away from RIG-I and thereby prevents mitochondrial antiviral immunity. In this study, we demonstrate that the proteasome PSMA7 (4) subunit associates with MAVS in vivo and in vitro. Expression of PSMA7 results in a potent inhibition of RIG-1 and MAVS-mediated IFN-β promoter activity; conversely, depletion of PSMA7 with small interference RNA enhances virus-induced type I IFN production, with consequent reduction of virus replication. Furthermore, a striking reduction in the abundance of endogenous MAVS with overexpressed PSMA7 was found and virus infection leads to transient increase in the endogenous PSMA7 protein level. Cumulatively, these results suggest that PSMA7 is a negative regulator of the MAVS-mediated innate immunity that probably serves to attenuate the establishment of an antiviral state during viral infection, highlighting the biological significance of PSMA7-MAVS association as an important cellular regulatory control.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by National Natural Science Foundation (30772605, 30700413, 30870500, and 30871276) and by the Beijing Natural Science Foundation (7092081).

² Y.J., T.S., and C.W. contributed equally to this work.

³ Address correspondence and reprint requests to Drs. Hui Zhong and Wei Shi, Beijing Institute of Biotechnology, Beijng, China. E-mail addresses: towall{at}yahoo.com and shiw{at}jlu.edu.cn

⁴ Abbreviations used in this paper: NLR, NOD-like receptor; CARD, caspase recruitment domain; siRNA, small interfering RNA; MOI, multiplicity of infection; VSV, vesicular stomatitis virus; UPS, ubiquitin-proteasome system; RIG-I, Retinoic Acid Induced Gene-1; MAVS, mitochondrial antiviral signaling; HA, hemagglutinin.