Abstract
African swine fever virus (ASFV) is an acute and persistent swine virus with a high economic burden that encodes multiple genes to evade host immune response. In this work, we have revealed that early viral protein UBCv1, the only known conjugating enzyme encoded by a virus, modulates innate immune and inflammatory signaling. Transient overexpression of UBCv1 impaired activation of NF-κB and AP-1 transcription factors induced by several agonists of these pathways. In contrast, activation of IRF3 and ISRE signaling upon stimulation with TRIFΔRIP, cGAS/STING or RIG-I-CARD remained unaltered. Experiments aimed at mapping UBCv1 inhibitory activity indicated that this viral protein acts upstream or at the level step of IKKβ. In agreement with this, UBCv1 was able to block p65 nuclear translocation upon cytokine stimulation, a key event in NF-ĸB signaling. Additionally, A549 stably transduced for UBCv1 showed a significant decrease in the levels of NF-ĸB dependent genes. Interestingly, despite the well-defined capacity of UBCv1 to conjugate ubiquitin chains, a mutant disabled for ubiquitylation activity retained similar immunomodulatory activity as the wild-type enzyme, suggesting that the two functions are segregated. Altogether these data suggest that ASFV UBCv1 manipulates the innate immune response targeting the NF-κB and AP-1 pathways and opens new questions about the multifunctionality of this enzyme.
Highlights
The initiation of the innate immune response is based on the recognition of invading viruses by host cells via the detection of pathogen-associated molecular patterns (PAMPs).To this end, a cooperative array of host-encoded pattern recognition receptors (PRRs) activates cellular signal transduction pathways to coordinate an effective response against viruses [1,2]
NF-κB is activated upon engagement of PRRs such as Toll-like receptors (TLRs) or the receptors of inflammatory cytokines such as tumor necrosis factor-α (TNF-α) or interleukin-1β (IL-1β)
The results presented here demonstrate that transient transfection of UBCv1 impairs the ability of host cells to activate NF-κB and Activating protein-1 (AP-1), but not Interferon regulatory factor 3 (IRF-3), sig
Summary
The initiation of the innate immune response is based on the recognition of invading viruses by host cells via the detection of pathogen-associated molecular patterns (PAMPs). A258R, a member of the MGF530 family, inhibits both IFNβ and NF-kB pathways of the type I IFN stimulation [23,25]; and the L86L open reading frame (ORF) encodes for a non-essential gene and has been described to interact with host protein IL-1β, the implications in innate immune response are unknown [26]. The ASFV I215L gene codes for the only known ubiquitin-conjugating enzyme encoded by a virus It is expressed very early during infection and it is able to associate with several classes of polyubiquitin chains. Viruses 2021, 13, 1160 naling pathways and that this activity maps upstream of the IKK complex These data indicate that UBCv1 is able to dampen inflammatory signaling in isolation irrespective of its ubiquitylating function and poses future questions about the multifunctionality of this protein
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