Poly(C)-binding protein 1 (PCBP1) mediates housekeeping degradation of mitochondrial antiviral signaling (MAVS)

Abstract

Mitochondrial antiviral signaling (MAVS) is a key adaptor in cellular antiviral innate immunity. We previously identified poly(C)-binding protein 2 (PCBP2) as a feedback inhibitor of MAVS that facilitates its degradation after viral infection, but little is known about the regulatory potential of poly(C)-binding protein 1 (PCBP1), which highly resembles PCBP2. Here we report that PCBP1 mediates housekeeping degradation of MAVS using the same mechanism as PCBP2 employs. Overexpression of PCBP1 impairs MAVS-mediated antiviral responses, while knockdown of PCBP1 exerts the opposite effect. The suppression is due to PCBP1-induced MAVS degradation. We observe that PCBP1 and PCBP2 show synergy in MAVS inhibition, but their expression patterns are distinct: PCBP1 is stably and abundantly expressed, while PCBP2 shows low basal expression with rapid induction after infection. Individual knockdown and subcellular fractionation analyses reveal that unlike the postinfection inhibitor PCBP2, PCBP1 continuously eliminates cellular MAVS. Our findings unravel a critical role of PCBP1 in regulating MAVS for both finetuning the antiviral immunity and preventing inflammation.

Poly(C)-Binding Protein 1, a Novel N pro -Interacting Protein Involved in Classical Swine Fever Virus Growth

“…PCBP1 was recently shown to reduce IFN induction through the degradation of mitochondrial antiviral signaling (MAVS) (30), demonstrating that PCBP1 proteins participate in innate immune signaling that specifically reduces antiviral responses in swine cells. Our experiment showed that ectopic/upregulated expression of PCBP1 alone reduced induction of the poly(I·C)-induced IFN-␤ expression, suggesting that enhanced CSFV replication in PK-15 cells (Fig.…”

“…Some of the KH domain superfamily proteins have recently been shown to play crucial roles in the innate immune response to viral infection (30,37). PCBPs belong to the KH domain superfamily, which is characterized by specific binding to both RNA and DNA (28).…”

“…One of these proteins, PCBP1 (Fig. 1), was selected for further study because it has been shown to be involved in the replication of several viruses (28)(29)(30). N pro interacts and colocalizes with PCBP1.…”

Smurf2 Negatively Modulates RIG-I–Dependent Antiviral Response by Targeting VISA/MAVS for Ubiquitination and Degradation

“…PCBP2 recruited the HECT domain-containing E3 ligase AIP4 to polyubiquitinate and degrade VISA, resulting in the abrogated antiviral immune responses (15). Interestingly, PCBP1, the highly homologous protein to PCBP2, mediates the degradation of VISA using the same mechanism as PCPB2 employs (25). TRIM25 promoted the K48-linked ubiquitination and degradation of VISA (26).…”

Ubiquitin in the activation and attenuation of innate antiviral immunity

“…3). RNF5 polyubiquitinates MAVS at Lys362 and Lys461, whereas the adjacent residues Lys371 and Lys420 are polyubiquitinated by AIP4 upon recruitment by poly(rC)-binding protein 1 (PCBP1) or PCBP2 (You et al, 2009;Zhong et al, 2010;Zhou et al, 2012). AIP4 additionally inhibits IFN-I as well as NF-κB activation by ubiquitinating the inhibitor of apoptosis protein 1 (cIAP1), targeting it for lysosomal degradation (Tigno-Aranjuez et al, 2013).…”