UBXN1 Interferes with Rig-I-like Receptor-Mediated Antiviral Immune Response by Targeting MAVS

Abstract

SUMMARY RNA viruses are sensed by RIG-I-like receptors (RLRs), which signal through a mitochondria-associated adaptor molecule, MAVS, resulting in systemic antiviral immune responses. Although RLR signaling is essential for limiting RNA virus replication, it must be stringently controlled to prevent damage from inflammation. We demonstrate here that among all tested UBX-domain-containing protein family members, UBXN1 exhibits the strongest inhibitory effect on RNA-virus-induced type I interferon response. UBXN1 potently inhibits RLR- and MAVS-induced, but not TLR3-, TLR4-, or DNA-virus-induced innate immune responses. Depletion of UBXN1 enhances virus-induced innate immune responses, including those resulting from RNA viruses such as vesicular stomatitis, Sendai, West Nile, and dengue virus infection, repressing viral replication. Following viral infection, UBXN1 is induced, binds to MAVS, interferes with intracellular MAVS oligomerization, and disrupts the MAVS/TRAF3/TRAF6 signalosome. These findings underscore a critical role of UBXN1 in the modulation of a major antiviral signaling pathway.

Mechanisms of MAVS Regulation at the Mitochondrial Membrane

“…This finding has been corroborated by more recent work that has uncovered a second TRAF3 binding site in MAVS corresponding to this same region [92]. In fact, a more recent study has reported that an ubiquitin regulatory X domain-containing protein (UBXN1) also negatively regulates MAVS by binding it and blocking its interaction with TRAF3/TRAF6 at the C-terminal binding site, further supporting the importance of this region in MAVS-mediated signaling [54]. Work is ongoing to determine the specific kinases responsible for the primary phosphorylation of MAVS that facilitates PLK1 binding.…”

Mitochondrial Control of Innate Immunity and Inflammation

“…The UBX-domain-containing protein UBXN1 inhibited RNA virus-mediated antiviral signaling by binding to the MAVS protein, preventing oligomerization thereof (67). Further study showed that the Smad ubiquitin regulatory factor (Smurf) 2 negatively regulated antiviral type I IFN responses by interacting with the MAVS protein, triggering proteasome-mediated degradation (68).…”

Ubiquitin-associated Domain-containing Ubiquitin Regulatory X (UBX) Protein UBXN1 Is a Negative Regulator of Nuclear Factor κB (NF-κB) Signaling

“…UBX domain-containing protein 1 (UBXN1) contains both the N-terminal UBA domain and the C-terminal UBX domain, and it was recently discovered to interfere with RIG-I-mediated antiviral immune response by targeting the mitochondrial antivirus-signaling protein (16). In this study, we used a small scale siRNA library that screened out UBXN1 as a negative regulator in TNF␣-triggered NF-B activation.…”