PEDV NSP8 inhibits IFN-III production induced by MAVS through downregulation of PEX13
Year: 2025
Type: article
Abstract: Porcine epidemic diarrhea virus (PEDV), an enteropathogenic coronavirus that causes severe intestinal disease in piglets, employs sophisticated strategies to subvert host antiviral immunity. While type III interferons (IFN-III) play a pivotal role in mucosal defense at intestinal epithelial barriers, the mechanisms underlying PEDV evasion of IFN-III signaling remain poorly understood. Given that peroxisomes serve as critical platforms for IFN-III signaling and that their abundance influences immune activation, we investigated the role of pexophagy in PEDV-mediated immune evasion. We demonstrated that the PEDV nonstructural protein NSP8 functions as a potent inhibitor of mitochondrial antiviral-signaling protein (MAVS)-dependent IFN-III production. Functional analyses revealed that NSP8 significantly reduces peroxisomal protein levels and promotes pexophagy. Mechanistically, mass spectrometry identified a direct interaction between NSP8 and PEX13. NSP8 also induces dose-dependent degradation of PEX13 via the autophagy-lysosomal pathway. This downregulation of PEX13 triggers ubiquitination of the peroxisomal import receptor PEX5, facilitating its recognition by the autophagy receptor NBR1 and the ubiquitin ligase PEX2, thereby promoting autophagic clearance of peroxisomes. Collectively, our findings reveal a novel immune evasion strategy in which PEDV exploits NSP8 to disrupt peroxisome homeostasis by targeting PEX13, thereby dismantling MAVS-dependent IFN-III antiviral signaling through pexophagy. IMPORTANCE: Porcine epidemic diarrhea virus (PEDV) NSP8 is a highly conserved protein that plays a crucial role in viral replication. Investigating the functional mechanisms of NSP8 contributes to a deeper understanding of PEDV pathogenesis and supports the development of antiviral strategies against coronaviruses. In this study, we elucidate how NSP8 suppresses type Ⅲ interferon (IFN-Ⅲ) production by promoting pexophagy through the downregulation of PEX13. We demonstrate that NSP8 directly interacts with PEX13 and enhances the ubiquitination of PEX5, leading to reduced peroxisome abundance and impaired mitochondrial antiviral-signaling protein (MAVS)-mediated IFN-Ⅲ signaling. These findings suggest that NSP8 hijacks the PEX13-dependent pexophagy pathway as a means of evading host antiviral defenses. This work provides critical insights into the interplay between viral proteins and host cellular machinery and highlights the NSP8-PEX13 axis as a promising target for therapeutic interventions aimed at enhancing antiviral immunity against PEDV and related coronaviruses.
Source: mBio
Institution: Nanjing Agricultural University
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,900
OpenAlex ID: W4415873201