Induction of GADD34 Is Necessary for dsRNA-Dependent Interferon-β Production and Participates in the Control of Chikungunya Virus Infection

Abstract

Nucleic acid sensing by cells is a key feature of antiviral responses, which generally result in type-I Interferon production and tissue protection. However, detection of double-stranded RNAs in virus-infected cells promotes two concomitant and apparently conflicting events. The dsRNA-dependent protein kinase (PKR) phosphorylates translation initiation factor 2-alpha (eIF2α) and inhibits protein synthesis, whereas cytosolic DExD/H box RNA helicases induce expression of type I-IFN and other cytokines. We demonstrate that the phosphatase-1 cofactor, growth arrest and DNA damage-inducible protein 34 (GADD34/Ppp1r15a), an important component of the unfolded protein response (UPR), is absolutely required for type I-IFN and IL-6 production by mouse embryonic fibroblasts (MEFs) in response to dsRNA. GADD34 expression in MEFs is dependent on PKR activation, linking cytosolic microbial sensing with the ATF4 branch of the UPR. The importance of this link for anti-viral immunity is underlined by the extreme susceptibility of GADD34-deficient fibroblasts and neonate mice to Chikungunya virus infection.

Function of monocytes and monocyte-derived macrophages in α1-antitrypsin deficiency

“…4e-h). In line with previous research [43,44], LPS significantly increased CHOP and GADD34 mRNA levels and the splicing of XBP1 mRNA. When we assessed GRP78 protein levels by western blot, we were unable to detect its increase in mw-2 ( fig.…”

γδ T Cells Play a Protective Role in Chikungunya Virus-Induced Disease

“…Although some host immune pathways have been implicated in the recognition of CHIKV and subsequent induction of protective and pathogenic responses (59,62,67,69,82,(92)(93)(94), the precise mediators and mechanisms of CHIKV pathogenesis are still relatively poorly understood. Given the prevalence of ␥␦ T cells in the skin, the primary site of CHIKV infection, and evidence that this T cell subset plays a role in the pathogenesis of other arboviruses (95)(96)(97)(98), we tested whether ␥␦ T cells played any role in the pathogenesis of CHIKV-induced disease.…”

Viperin restricts chikungunya virus replication and pathology

“…This intricate interplay between the innate host response and virus infection was also demonstrated to involve GADD34, a subunit of protein phosphatase 1 (PP1) induced in response to CHIKV and ER stress to control virus infection Furthermore, targeting the N-terminal amphipathic α-helical domain of viperin alone to the ER was demonstrated to be sufficient for inhibition of protein secretion, possibly due to the disrupted ER structure and integrity (43). However, whether the antiviral function of viperin against CHIKV is mediated in a (60,61). Thus, it is plausible that targeting of the N-terminal amphipathic α-helical domain of viperin to ER could represent a mechanism to control CHIKV, as viperin mutants lacking the ER-targeting N-terminal amphipathic α-helical domain displayed a compromised ability to inhibit CHIKV infection.…”