Herpes simplex virus 2(HSV-2)is a major pathogen causing neonatal herpes and increasing the risk of human immunodeficiency virus 1(HIV-1)infection.However,the mechanisms underlying host restriction of HSV-2 infection ...Herpes simplex virus 2(HSV-2)is a major pathogen causing neonatal herpes and increasing the risk of human immunodeficiency virus 1(HIV-1)infection.However,the mechanisms underlying host restriction of HSV-2 infection are still not fully understood.The ubiquitously expressed transcript isoform 2(UXT-V2),anα-type prefoldin protein,functions as a versatile transcription factor associated with numerous human tumors,but its role in viral infection remains unclear.In this study,we found that ectopic expression of UXT-V2 significantly inhibited HSV-2 replication,while knockout of endogenously expressed UXT-V2 promoted HSV-2 proliferation.Further analysis revealed that UXT-V2 restricts HSV-2 replication independent of its role in regulating NF-κB.In the context of HSV--2 infection or in viral glycoprotein B(gB)-transfected cells,UXT-V2 facilitates K48-linked ubiquitination of gB,leading to its degradation via the proteasome pathway,thereby inhibiting viral replication.Furthermore,we identified that UXT-V2 interacts with gB,recruiting the E3 ligase TRIM21 to facilitate K48-linked ubiquitination of gB.HSV-2,in turn,reduces the abundance of UXT-V2 proteins both in vitro and in mice,highlighting the complexity of HSV-2-host interactions.Collectively,our findings,for the first time,demonstrate an anti-HSV-2 role of UXT-V2,unveiling a novel host immune defense mechanism involved in regulating glycoprotein homeostasis.展开更多
基金supported by the National Natural Science Foundation of China(82472272 and 82171736)the National Key Research and Development Program of China(2022YFC2304301 and 2023YFC2306600).
文摘Herpes simplex virus 2(HSV-2)is a major pathogen causing neonatal herpes and increasing the risk of human immunodeficiency virus 1(HIV-1)infection.However,the mechanisms underlying host restriction of HSV-2 infection are still not fully understood.The ubiquitously expressed transcript isoform 2(UXT-V2),anα-type prefoldin protein,functions as a versatile transcription factor associated with numerous human tumors,but its role in viral infection remains unclear.In this study,we found that ectopic expression of UXT-V2 significantly inhibited HSV-2 replication,while knockout of endogenously expressed UXT-V2 promoted HSV-2 proliferation.Further analysis revealed that UXT-V2 restricts HSV-2 replication independent of its role in regulating NF-κB.In the context of HSV--2 infection or in viral glycoprotein B(gB)-transfected cells,UXT-V2 facilitates K48-linked ubiquitination of gB,leading to its degradation via the proteasome pathway,thereby inhibiting viral replication.Furthermore,we identified that UXT-V2 interacts with gB,recruiting the E3 ligase TRIM21 to facilitate K48-linked ubiquitination of gB.HSV-2,in turn,reduces the abundance of UXT-V2 proteins both in vitro and in mice,highlighting the complexity of HSV-2-host interactions.Collectively,our findings,for the first time,demonstrate an anti-HSV-2 role of UXT-V2,unveiling a novel host immune defense mechanism involved in regulating glycoprotein homeostasis.
