DNAJB1/HSP40 Suppresses Melanoma Differentiation-Associated Gene 5-Mitochondrial Antiviral Signaling Protein Function in Conjunction with HSP70

Abstract

Melanoma differentiation-associated gene 5 (MDA5) is a pattern recognition receptor that recognizes cytoplasmic viral double-stranded RNA (dsRNA) and initiates rapid innate antiviral responses. MDA5 forms a filament-like multimer along the dsRNA leading to oligomerization, which in turn activates the adaptor protein mitochondrial antiviral signaling protein (MAVS) to provide a signal platform for the induction of type I interferon (IFN) and proinflammatory cytokines. The conformational switch of MDA5 causes antiviral defense, but excessive activation of the MDA5-MAVS pathway may result in autoimmune diseases. The regulatory mechanisms of MDA5 activation remain largely unknown. By yeast 2-hybrid, we identified DNAJB1, a member of the HSP40 (heat shock protein 40) family, as an MDA5-binding protein. HSP40s usually cowork with HSP70s. We found that dsRNA stimulation with physiological conditions upregulated the expression levels of DNAJB1 and HSP70; then the proteins were coupled and translocated into the stress granules, where MDA5 encounters dsRNA. DNAJB1 disrupted MDA5 multimer formation, resulting in the suppression of type I IFN induction. The disruption of endogenous DNAJB1 increased MDA5- and MAVS-mediated IFN promoter activation and rendered cells virus resistant. HSP70 inhibitor also enhanced the IFN-inducing function of MDA5 and MAVS. These results suggest that the DNAJB1-HSP70 complex functions for the natural maintenance of RNA sensing by interacting with MDA5/MAVS.

Cold Exposure-Induced Up-Regulation of Hsp70 Positively Regulates PEDV mRNA Synthesis and Protein Expression In Vitro

“…The induction may occur indirectly through the production of a large number of unfolded proteins during stress. Indeed, Hsp70 is involved in many cellular processes, such as cell cycle, apoptosis, and cellular innate immunity pathways, which is frequently diverted by viruses for their benefits [11,[41][42][43]. Induction of the Hsp70 is a specific virus function that ensures proper synthesis of viral proteins and virions, thus stress proteins may be important for virus replication [44].…”

Dance with the Devil: Stress Granules and Signaling in Antiviral Responses

“…DNAJ heat shock protein family (Hsp40) member B1 (DNAJB1), a member of the Hsp40 family, was identified as an interactor of MDA5 that negatively regulates MDA5-MAVS signaling. Upon poly(I:C) treatment, DNAJB1 in conjunction with Hsp70 was found to co-localize with SG markers and the mitochondrial membrane, negatively affecting MDA5 oligomerization and MAVS aggregation [247]. If and how the co-localization of MDA5 together with the DNAJB1-Hsp70 complex or RIOK3 within SGs affects MDA5-MAVS signaling still needs to be investigated.…”

Heat Shock Proteins: Agents of Cancer Development and Therapeutic Targets in Anti-Cancer Therapy

“…HSP40 belongs to DNAJ family subcategorized into three subclasses, which are DnaJA (DNAJA), DnaJB (DNAJB), and DnaJC (DNAJC) [6]. HSP40 assists in protein folding, unfolding, translation, translocation, and degradation [11,25,26], as well as ATPase activity of HSP70 [27]. Many of the HSP40 family members are overexpressed in numerous human cancer types, such as colorectal, gastric, and lung cancers [28][29][30][31].…”