The nucleolar protein GLTSCR2 is required for efficient viral replication.

Peng Wang,Xiao-Jia Wang,Shi-Chong Han,Cui-Cui Li,Xiao-Jun Wang,Wen Meng

doi:10.1038/srep36226

Abstract

Glioma tumor suppressor candidate region gene 2 protein (GLTSCR2) is a nucleolar protein. In the investigation of the role of GLTSCR2 that played in the cellular innate immune response to viral infection, we found GLTSCR2 supported viral replication of rhabdovirus, paramyxovirus, and coronavirus in cells. Viral infection induced translocation of GLTSCR2 from nucleus to cytoplasm that enabled GLTSCR2 to attenuate type I interferon IFN-β and support viral replication. Cytoplasmic GLTSCR2 was able to interact with retinoic acid-inducible gene I (RIG-I) and the ubiquitin-specific protease 15 (USP15), and the triple interaction induced USP15 activity to remove K63-linked ubiquitination of RIG-I, leading to attenuation of RIG-I and IFN-β. Blocking cytoplasmic translocation of GLTSCR2, by deletion of its nuclear export sequence (NES), abrogated its ability to attenuate IFN-β and support viral replication. GLTSCR2-mediated attenuation of RIG-I and IFN-β led to alleviation of host cell innate immune response to viral infection. Our findings suggested that GLTSCR2 contributed to efficient viral replication, and GLTSCR2 should be considered as a potential target for therapeutic control of viral infection.

Highlights

Innate immunity is critical for defending the host from pathogens, and type I interferon (IFN) is the core of cellular antiviral response[1,2,3,4,5]
To investigate whether GLTSCR2 might play any role in viral replication, we used small interfering RNA to knock down GLTSCR2 in cells, followed by infection with Rhabdoviridae vesicular stomatitis virus (VSV), Paramyxoviridae Newcastle disease virus (NDV), and Coronaviridae infectious bronchitis virus (IBV)
To investigate if viral infection might modulate GLTSCR2 level in cells, we studied the timecourse of GLTSCR2 during VSV infection, and we detected that GLTSCR2 level was not significantly affected by viral infection (Fig. 1b), indicating the endogenous level of GLTSCR2 was sufficient to support viral replication

Summary

Introduction

Innate immunity is critical for defending the host from pathogens, and type I interferon (IFN) is the core of cellular antiviral response[1,2,3,4,5]. We detected that increases of ectopically expressed GLTSCR2 resulted in decreasing NF-κB-dependent promoter activity in cells infected with either SeV or VSV (Fig. 3b). Under the same experimental condition, electrophoretically separated proteins from HEK293T (−) or 293T sh-GLT (+) cells infected with VSV were analyzed by immunoblotting with specific antibodies to detect p-IRF3, IRF3, with actin as a control (right).

Results

Conclusion