Defining the proteolytic landscape during enterovirus infection

Abstract

Viruses cleave cellular proteins to remodel the host proteome. The study of these cleavages has revealed mechanisms of immune evasion, resource exploitation, and pathogenesis. However, the full extent of virus-induced proteolysis in infected cells is unknown, mainly because until recently the technology for a global view of proteolysis within cells was lacking. Here, we report the first comprehensive catalog of proteins cleaved upon enterovirus infection and identify the sites within proteins where the cleavages occur. We employed multiple strategies to confirm protein cleavages and assigned them to one of the two enteroviral proteases. Detailed characterization of one substrate, LSM14A, a p body protein with a role in antiviral immunity, showed that cleavage of this protein disrupts its antiviral function. This study yields a new depth of information about the host interface with a group of viruses that are both important biological tools and significant agents of disease.

Polyamine Analog Diethylnorspermidine Restricts Coxsackievirus B3 and Is Overcome by 2A Protease Mutation In Vitro

“…CVB3 encodes two distinct proteases, 2A and 3C. These two proteases catalyze the majority of cleavage of the viral polyprotein [ 23 , 24 , 25 ]. Upon entry into the cell, CVB3’s RNA genome is translated by the host cell’s machinery, synthesizing the polyprotein [ 23 , 24 , 25 ].…”

“…These two proteases catalyze the majority of cleavage of the viral polyprotein [ 23 , 24 , 25 ]. Upon entry into the cell, CVB3’s RNA genome is translated by the host cell’s machinery, synthesizing the polyprotein [ 23 , 24 , 25 ]. 2A performs the primary cleavage of the polyprotein, and 3C catalyzes subsequent polyprotein cleavage [ 23 , 25 ].…”

Inhibition of Type III Interferon Expression in Intestinal Epithelial Cells—A Strategy Used by Coxsackie B Virus to Evade the Host’s Innate Immune Response at the Primary Site of Infection?

“…CVB host immune evasion strategies have been described, including the prevention of type I IFN production [30] and early cell death [27,31]. Recent studies have begun to document the scale of disruption that enterovirus encoded proteases can have on host cells through the cleavage of many cellular proteins [29,32]. It is not currently known, however, whether CVBs can also attenuate type III IFN production in IECs, as seen in our experiments conducted in HeLa cells [33].…”

“…This lack of response led us to wonder whether CVBs have the capacity to interfere with the ability of IECs to produce IFNs. Many viruses, including CVBs, have developed strategies to evade the host's immune response in order to favor their own replication, including blocking type I and III IFN production and/or signaling [26][27][28][29][30][31]. It has been suggested that the CVB encoded proteases 2A pro and 3C pro are involved in the degradation of proteins involved in virus recognition and the induction of a type I IFN response [30,41].…”

“…As host cells have developed methods to control viral infections, many viruses in turn have evolved sophisticated mechanisms to evade the host's immune responses. These include targeting pathways involved in type I IFN production and signaling, modulating ISGs, preventing the cell from undergoing apoptosis, and inhibiting stress granule formation [26][27][28][29]. CVB host immune evasion strategies have been described, including the prevention of type I IFN production [30] and early cell death [27,31].…”