Author

Jie Sun

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Aug 2026

Molecular characterization and heterodimerization of three type I interferon receptor subunits (CaCRFB1, CaCRFB2, CaCRFB5) in the humpback grouper (Cromileptes altivelis).

Type I interferons (IFNs) are a class of pleiotropic cytokines that play a pivotal role in host defense against pathogenic invaders by binding with specific heterodimeric receptors. Among teleosts, these receptors consist of diverse subunits, including CRFB1, CRFB2, and CRFB5, whereas their pairing patterns and structural basis of interactions remain ill-defined. In this study, we identified and characterized three type I IFN receptor genes (CaCRFB1, CaCRFB2, and CaCRFB5) in the humpback grouper (Cromileptes altivelis), all sharing a common architecture of two extracellular FNIII domains. Furthermore, all three CaCRFB genes exhibited not only constitutive expression across all examined tissues but also significant transcriptional upregulation in response to poly I:C, LPS and pathogenic challenges (Vibrio harveyi and nervous necrosis virus), highlighting their active involvement in innate immunity. To elucidate their assembly mechanisms, we integrated molecular docking with co-immunoprecipitation (Co-IP) assays targeting their extracellular domains. Our results validated the canonical heterodimerization of the short-chain CaCRFB5 with both long-chain subunits (CaCRFB1 and CaCRFB2) as well as a noncanonical interaction of CaCRFB1/CaCRFB2, suggesting a more intricate receptor pairing in teleosts. Structural interface analysis revealed that these interactions are principally driven by electrostatic forces, including hydrogen bonds and salt bridges. Intriguingly, while the membrane-proximal FNIII domain II mediates canonical interactions (CaCRFB1/CaCRFB5 and CaCRFB2/CaCRFB5), it is the membrane-distal FNIII domain I that orchestrates the noncanonical CaCRFB1/CaCRFB2 pairing. These findings shed light on the structural basis of receptor heterodimerization, enriching the understanding of the teleost type I IFN system.

Han Zhang, Ting Wu, Ying Chen et al. · Developmental and Comparativ... · 0 citations

Open access Jul 2026

MMF inhibits poxvirus infection by disrupting IMPDH2 interaction with USP5 and inducing its rod-and-ring assemblies

Monkeypox virus (MPXV), a pathogenic orthopoxvirus, has caused major outbreaks and emerged as a global public health threat. Although antivirals approved for smallpox are used therapeutically against monkeypox, their clinical utility is limited by drug availability and emerging resistance. The conserved strategy by which viruses remodel host nucleotide metabolism to secure biosynthetic precursors for replication and spread has emerged as a pivotal target for the development of broad-spectrum antiviral therapeutics. In this study, leveraging the high genetic and biological similarity between vaccinia virus (VACV) and MPXV, we employed VACV as a surrogate model to screen 10 FDA-approved inhibitors targeting nucleotide metabolism enzymes, aiming to identify potential novel inhibitors against MPXV. Mycophenolate mofetil (MMF), an inosine 5′-monophosphate dehydrogenase type II (IMPDH2) inhibitor, displayed potent inhibition effects against both VACV and MPXV. Subsequent downstream time-course studies revealed that MMF targets a post-entry stage of the viral replication cycle. Mechanistic studies suggest that MMF inhibits IMPDH2 activity by suppressing ubiquitin-specific protease 5 (USP5)-mediated deubiquitination of IMPDH2 and inducing rod-and-ring (R&R) assembly, leading to reducing dNTP pools and enhancing antiviral effects. In conclusion, our findings demonstrate that MMF is an effective antiviral drug against VACV and MPXV infection and establish a host-directed therapeutic strategy to combat future orthopoxvirus outbreaks.

Qian Sun, Kesen Liu, Wandi Cao et al. · Virologica Sinica · 0 citations