Abstract:Hepatitis C virus (HCV) replication involves many viral and host factors. Host factor SPRY domain- and SOCS box-containing protein 2(SPSB2) belongs to SPSB family, and it recruits target proteins by the SPRY domain and forms E3 ubiquitin ligase complexes by the SOCS box. As an adaptor protein, it can regulate the host’s response to infection, but little is known about whether SPSB2 plays a role in HCV replication. In the present study, we found that HCV infection significantly upregulated the mRNA and protein … Show more
“…SPSB2 does recruit E3 ubiquitin ligase complex to polyubiquitinate iNOS by interacting with its N-terminus, thus determining proteasome activation and subsequent increase in NO production [60] . Also, SPSB2 can exert an antiviral function by binding structural protein E1 and nonstructural protein 5A (NS5A) from Hepatitis C Virus (HCV), inhibiting its replication [61] . Fig.…”
“…SPSB2 does recruit E3 ubiquitin ligase complex to polyubiquitinate iNOS by interacting with its N-terminus, thus determining proteasome activation and subsequent increase in NO production [60] . Also, SPSB2 can exert an antiviral function by binding structural protein E1 and nonstructural protein 5A (NS5A) from Hepatitis C Virus (HCV), inhibiting its replication [61] . Fig.…”
“…In total we obtained population level variation for CD4 plus 15 other loci (six upstream and nine downstream). Four loci were removed from analysis because they have previously been shown to directly interact with a viral protein ( USP5 and SPSB2 ; (Jia et al, 2020; Rathore et al, 2020; Wang et al, 2019; Zhang et al, 2021)) or non-human primate sequencing reads did not map well with the human reference due to repetitive sequence ( LAG3 and P3H3 ). Coding loci included in this study (in order 5’ to 3’) are: ZNF384 , PIANP , COPS7A , MLF2 , PTMS , CD4 , GPR162 , GNB3 , CDCA3 , TPI1 , LRRC23 , and ENO2 .…”
Simian immunodeficiency viruses (SIVs) comprise a large group of primate lentiviruses that endemically infect African monkeys. HIV-1 spilled over to humans from this viral reservoir, but the spillover did not occur directly from monkeys to humans. Instead, a key event was the introduction of SIVs into great apes, which then set the stage for infection of humans. Here, we investigate the role of the lentiviral entry receptor, CD4, in this key and fateful event in the history of SIV/HIV emergence. First, we reconstructed and tested ancient forms of CD4 at two important nodes in ape speciation, prior to the infection of chimpanzees and gorillas with these viruses. These ancestral CD4s fully supported entry of diverse SIV isolates related to the virus(es) that made this initial jump to apes. In stark contrast, modern chimpanzee and gorilla CD4s are more resistant to these viruses. To investigate how this resistance in CD4 was gained, we acquired CD4 sequences from 32 gorilla individuals of 2 species, and identified alleles that encode 8 unique CD4 proteins. Function testing of these identified allele-specific CD4 differences in susceptibility to virus entry. By engineering single point mutations from gorilla CD4 alleles into a permissive human CD4 receptor, we demonstrate that acquired SNPs in gorilla CD4 did convey resistance to virus entry. We provide a population genetic analysis to support the theory that selection is acting in favor of more and more resistant CD4 alleles in apes with endemic SIV infection (gorillas and chimpanzees), but not in other ape species (bonobo and orangutan) that lack SIV infections. Taken together, our results show that SIV has placed intense selective pressure on ape CD4, acting to drive the generation of SIV-resistant CD4 alleles in chimpanzees and gorillas.
“…As an indispensable role in consisting replication complex, HCV NS5A is also a new ubiquitinated protein (Wang et al, 2016a(Wang et al, , 2019Yang et al, 2016;Pham et al, 2019). During HCV infection, the expression level Ubiquitin-conjugating enzyme E2S (UBE2S) and Lys11 chains were suppressed significantly, which made HCV-infected cells DNA damage to promote its replication (Pham et al, 2019).…”
Section: The Ubiquitination Of Ns5amentioning
confidence: 99%
“…SPRY domain-and SOCS box-containing protein 2 (SPSB2), the adaptor protein of ECS (Elongin B/C-Cullin 5-SOCS box protein) E3 ligase complex, can recruit target protein to ubiquitinate and degrade them (Kuang et al, 2010). SPSB2 indirectly targets NS5A in SoCS box-dependent manner to promote NS5A ubiquitination and degradation in proteasomedependent manner, and significantly inhibits HCV replication (Wang et al, 2019; Figure 5).…”
Ubiquitination is a reversible protein post-translational modification that regulates various pivotal physiological and pathological processes in all eukaryotes. Recently, the antiviral immune response is enhanced by the regulation of ubiquitination. Intriguingly, Flaviviridae viruses can ingeniously hijack the ubiquitination system to help them survive, which has become a hot topic among worldwide researchers. The Flaviviridae family members, such as HCV and CSFV, can cause serious diseases of humans and animals around the world. The multiple roles of ubiquitination involved in the life cycle of Flaviviridae family would open new sight for future development of antiviral tactic. Here, we discuss recent advances with regard to functional roles of ubiquitination and some ubiquitin-like modifications in the life cycle of Flaviviridae infection, shedding new light on the antiviral mechanism research and therapeutic drug development.
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