Global Reprogramming of Host SUMOylation during Influenza Virus Infection.

Aislynn Taggart,Antonio M. Lopes,Filip Golebiowski,Patricia Domingues,Benjamin G. Hale,Ronald T. Hay,Michael H. Tatham

doi:10.1016/j.celrep.2015.10.001

Aislynn Taggart, Antonio M. Lopes + Show 5 more

Open Access

https://doi.org/10.1016/j.celrep.2015.10.001

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Abstract

SummaryDynamic nuclear SUMO modifications play essential roles in orchestrating cellular responses to proteotoxic stress, DNA damage, and DNA virus infection. Here, we describe a non-canonical host SUMOylation response to the nuclear-replicating RNA pathogen, influenza virus, and identify viral RNA polymerase activity as a major contributor to SUMO proteome remodeling. Using quantitative proteomics to compare stress-induced SUMOylation responses, we reveal that influenza virus infection triggers unique re-targeting of SUMO to 63 host proteins involved in transcription, mRNA processing, RNA quality control, and DNA damage repair. This is paralleled by widespread host deSUMOylation. Depletion screening identified ten virus-induced SUMO targets as potential antiviral factors, including C18orf25 and the SMC5/6 and PAF1 complexes. Mechanistic studies further uncovered a role for SUMOylation of the PAF1 complex component, parafibromin (CDC73), in potentiating antiviral gene expression. Our global characterization of influenza virus-triggered SUMO redistribution provides a proteomic resource to understand host nuclear SUMOylation responses to infection.

Highlights

Reversible posttranslational modification of proteins provides cells with a rapid and dynamic mechanism to modulate proteome functionality in response to many stimuli, including pathogen invasion
Using quantitative proteomics to compare stress-induced SUMOylation responses, we reveal that influenza virus infection triggers unique re-targeting of small ubiquitin-like modifiers (SUMOs) to 63 host proteins involved in transcription, mRNA processing, RNA quality control, and DNA damage repair
Mechanistic studies further uncovered a role for SUMOylation of the PAF1 complex component, parafibromin (CDC73), in potentiating antiviral gene expression

Summary

Introduction

Reversible posttranslational modification of proteins provides cells with a rapid and dynamic mechanism to modulate proteome functionality in response to many stimuli, including pathogen invasion. With clear parallels to the SUMOylation response triggered by environmental stresses, a nuclear-replicating HSV-1 mutant lacking the ability to degrade SUMO-modified proteins induces increased SUMO conjugate formation during infection and is restricted by an active SUMO system (Boutell et al, 2011). This suggests that cells sense DNA virus infection stress in the nucleus and (in the absence of a pathogen-encoded antagonist) respond by enhancing SUMOylation of certain targets to suppress replication

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