Abstract
Enterovirus 71 (EV71) is the main causative agent of hand, foot and mouth disease (HFMD), which induces significantly elevated levels of cytokines and chemokines, leading to local or system inflammation and severe complications, whereas the underlying regulatory mechanisms and the inflammatory pathogenesis remain elusive. ARRDC4 is one member of arrestins family, having important roles in glucose metabolism and G-protein-coupled receptors (GPCRs) related physiological and pathological processes, however, the function of ARRDC4 in innate immune system is largely unknown. Here we identified that ARRDC4 expression was increased after EV71 infection in THP-1-derived macrophages and verified in EV71-infected HFMD patients and the healthy candidates. The expression level of ARRDC4 was positively correlated with the serum concentration of IL-6, TNF-α and CCL3 in clinical specimens. ARRDC4 interacted with MDA5 via the arrestin-like N domain, and further recruited TRIM65 to enhance the K63 ubiquitination of MDA5, resulting in activation of the downstream innate signaling pathway and transcription of proinflammatory cytokines during EV71 infection. Our data highlight new function of ARRDC4 in innate immunity, contributing to the better understanding about regulation of MDA5 activation after EV71 infection, and also suggest ARRDC4 may serve as a potential target for intervention of EV71-induced inflammatory response.
Highlights
Enterovirus 71 (EV71) is a single positive-stranded RNA virus belonging to the picornaviridae family
ARRDC4 interacted with melanoma differentiation-associated gene 5 (MDA5) and promoted K63 ubiquitination of MDA5 via TRIM65, enhanced MDA5-dependent signaling pathways, leading to strengthening of cytokines production in anti-EV71 innate immune response
These results indicate that ARRDC4 may be involved in EV71-induced immune response
Summary
Enterovirus 71 (EV71) is a single positive-stranded RNA virus belonging to the picornaviridae family. Much of the concerns are about the β-arrestins, especially in immune and inflammatory responses.[20] β-Arrestin can negatively regulate LPS triggered proinflammatory cytokines production,[21] and have moderates roles in antiviral innate immune response.[22] ARRDC4 is one member of α-arrestins, which has the arrestin-like structure and highly conserved polyproline (PY) motif in the C-terminal tail.[19] ARRDC4 participates in glucose metabolism,[23] and exhibits more varied functions through recruiting some E3 ligases to induce ubiquitination of GPCRs.[24] Interestingly, it has been suggested that α-arrestin and β-arrestin may hetero-associate and have coordinated or antagonistic functions depending on context,[25] the function of ARRDC4 in immune response is largely unknown, deserves fuller exploration. ARRDC4 interacted with MDA5 and promoted K63 ubiquitination of MDA5 via TRIM65, enhanced MDA5-dependent signaling pathways, leading to strengthening of cytokines production in anti-EV71 innate immune response
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