Proteasomal degradation of human SERINC4: A potent host anti-HIV-1 factor that is antagonized by nef

Qiu, Xusheng; Eke, Ifeanyichukwu E.; Johnson, Silas F.; Ding, Chan; Zheng, Yong Hui

doi:10.1016/j.crviro.2020.100002

Cited by 9 publications

(9 citation statements)

References 22 publications

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“…The viruses were collected, and infectivity assays were performed as reported previously ( 20 , 21 ). In agreement with earlier reports ( 24 – 26 ), we confirmed that the inhibition of nef-defective-HIV-1 infectivity is conserved among four human SERINCs ; SERINC 2 is the only paralog that shows no detectable activity against the virus ( Fig. 1B ).…”

Section: Resultssupporting

confidence: 93%

Coelacanth SERINC2 Inhibits HIV-1 Infectivity and Is Counteracted by Envelope Glycoprotein from Foamy Virus

Ramdas

Bhardwaj

Singh

et al. 2021

J Virol

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SERINC5 restricts nef-defective HIV-1 by affecting early steps of the virus life cycle. Distant retroviruses with a wide host-range encode virulent factors in response to the challenge by SERINC5. Yet, the evolutionary origins of this anti-retroviral activity, its prevalence among the paralogs, and its ability to target retroviruses remain understudied. In agreement with previous studies, we find that four human SERINC paralogs inhibit nef-defective HIV-1, with SERINC2 being an exception. Here, we demonstrate that this lack of activity in human SERINC2 is associated with its post-whole genome duplication (WGD) divergence, as evidenced by the ability of pre-WGD orthologs from yeast, fly, and a post-WGD-proximate SERINC2 from coelacanth to inhibit the virus. Intriguingly, Nef is unable to counter coelacanth SERINC2, indicating that such activity was directed towards other retroviruses found in coelacanth (like foamy viruses). However, foamy-derived vectors are intrinsically resistant to the action of SERINC2, and we show that the foamy virus envelope confers this resistance by affecting its steady-state levels. Our study highlights an ancient origin of anti-retroviral activity in SERINCs and a hitherto unknown interaction with a foamy virus. Importance SERINC5 constitutes a critical barrier to the propagation of retroviruses as highlighted by parallel emergence of anti-SERINC5 activities among distant retroviral lineages. Therefore, understanding the origin and evolution of these host factors will provide key information about virus-host relationships that can be exploited for future drug development. Here we show that SERINC5-mediated nef-defective HIV-1 infection inhibition is evolutionarily conserved. SERINC2 from coelacanth restricts HIV-1 and it was functionally adapted to target foamy viruses. Our findings provide insights into the evolutionary origin of anti-retroviral activity in SERINC gene family and uncover the role of SERINCs in shaping the long-term conflicts between retroviruses and their hosts.

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Section: Resultssupporting

confidence: 93%

Coelacanth SERINC2 Inhibits HIV-1 Infectivity and Is Counteracted by Envelope Glycoprotein from Foamy Virus

Ramdas

Bhardwaj

Singh

et al. 2021

J Virol

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“…It can modulate the autophagy pathway of our RV strain, which will need further detailed research, whereas PARD6B was shared in the cancer pathways ( Cunliffe et al, 2012 ). COG6 and SERINC4 have been suggested to be inhibitors of HIV-1 replication ( Liu et al, 2014 ; Qiu et al, 2020 ), while the expression of AZGP1 , which has been reported to be associated with HPV status, was significantly high ( Poropatich et al, 2019 ). ERAL1 suppressed RNA virus infection by facilitating RIG-I-like receptor signaling ( Li et al, 2021 ), while ORMDL3 was reported to be regulated by IRF-3 as a result of RSV infection by direct binding to the promoter of ORMDL3 ( Wang et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

MicroRNA Profile of MA-104 Cell Line Associated With the Pathogenesis of Bovine Rotavirus Strain Circulated in Chinese Calves

Elkady

Chen

et al. 2022

Front. Microbiol.

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Bovine rotavirus (BRV) causes massive economic losses in the livestock industry worldwide. Elucidating the pathogenesis of BRV would help in the development of more effective measures to control BRV infection. The MA-104 cell line is sensitive to BRV and is thereby a convenient tool for determining BRV–host interactions. Thus far, the role of the microRNAs (miRNAs) of MA-104 cells during BRV infection is still ambiguous. We performed Illumina RNA sequencing analysis of the miRNA libraries of BRV-infected and mock-infected MA-104 cells at different time points: at 0 h post-infection (hpi) (just after 90 min of adsorption) and at 6, 12, 24, 36, and 48 hpi. The total clean reads obtained from BRV-infected and uninfected cells were 74,701,041 and 74,184,124, respectively. Based on these, 579 were categorized as known miRNAs and 144 as novel miRNAs. One hundred and sixty differentially expressed (DE) miRNAs in BRV-infected cells in comparison with uninfected MA-104 cells were successfully investigated, 95 of which were upregulated and 65 were downregulated. The target messenger RNAs (mRNAs) of the DE miRNAs were examined by bioinformatics analysis. Functional annotation of the target genes with Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) suggested that these genes mainly contributed to biological pathways, endocytosis, apoptotic process, trans-Golgi membrane, and lysosome. Pathways such as the mammalian target of rapamycin (mTOR) (mml-miR-486-3p and mml-miR-197-3p), nuclear factor kappa B (NF-κB) (mml-miR-204-3p and novel_366), Rap1 (mml-miR-127-3p), cAMP (mml-miR-106b-3p), mitogen-activated protein kinase (MAPK) (mml-miR-342-5p), T-cell receptor signaling (mml-miR-369-5p), RIG-I-like receptor signaling (mml-miR-504-5p), AMP-activated protein kinase (AMPK) (mml-miR-365-1-5p), and phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) signaling (mml-miR-299-3p) were enriched. Moreover, real-time quantitative PCR (qPCR) verified the expression profiles of 23 selected DE miRNAs, which were consistent with the results of deep sequencing, and the 28 corresponding target mRNAs were mainly of regulatory pathways of the cellular machinery and immune importance, according to the bioinformatics analysis. Our study is the first to report a novel approach that uncovers the impact of BRV infection on the miRNA expressions of MA-104 cells, and it offers clues for identifying potential candidates for antiviral or vaccine strategies.

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“…Serine incorporators (SERINC) 3 and 5 have been identified as restriction factors against retroviruses [17,18,112] and against hepatitis B virus (HBV) [113]. Recently, the antiviral action of SERINC4 has also been established against HIV-1 [114]. These factors belong to a family of five proteins, TMS-TDE family, characterized by 10 to 11 transmembrane domains (Figure 2) [115].…”

Section: Ubiquitination Of Serinc Proteins Lead To Its Degradation Upon Infectionmentioning

confidence: 99%

“…Ubiquitination of SERINC proteins seems to be among these strategies. Indeed, SERINC3, 4 and 5 are counteracted by the accessory protein Nef (negative regulatory factor) encoded by HIV-1 [17,18,114], by the glycosylated Gag (glycoGag) of MLV [31] and by the small accessory protein S2 of equine infectious anemia virus (EIAV) [118]. These viral proteins all prevent SERINC5 incorporation into viral particles by inducing its ubiquitination and therefore downregulating their cell surface expression.…”

Section: Ubiquitination Of Serinc Proteins Lead To Its Degradation Upon Infectionmentioning

confidence: 99%

Regulation of Viral Restriction by Post-Translational Modifications

Chamontin

Bossis

Nisole

et al. 2021

Viruses

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Intrinsic immunity is orchestrated by a wide range of host cellular proteins called restriction factors. They have the capacity to interfere with viral replication, and most of them are tightly regulated by interferons (IFNs). In addition, their regulation through post-translational modifications (PTMs) constitutes a major mechanism to shape their action positively or negatively. Following viral infection, restriction factor modification can be decisive. Palmitoylation of IFITM3, SUMOylation of MxA, SAMHD1 and TRIM5α or glycosylation of BST2 are some of those PTMs required for their antiviral activity. Nonetheless, for their benefit and by manipulating the PTMs machinery, viruses have evolved sophisticated mechanisms to counteract restriction factors. Indeed, many viral proteins evade restriction activity by inducing their ubiquitination and subsequent degradation. Studies on PTMs and their substrates are essential for the understanding of the antiviral defense mechanisms and provide a global vision of all possible regulations of the immune response at a given time and under specific infection conditions. Our aim was to provide an overview of current knowledge regarding the role of PTMs on restriction factors with an emphasis on their impact on viral replication.

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Proteasomal degradation of human SERINC4: A potent host anti-HIV-1 factor that is antagonized by nef

Cited by 9 publications

References 22 publications

Coelacanth SERINC2 Inhibits HIV-1 Infectivity and Is Counteracted by Envelope Glycoprotein from Foamy Virus

Coelacanth SERINC2 Inhibits HIV-1 Infectivity and Is Counteracted by Envelope Glycoprotein from Foamy Virus

MicroRNA Profile of MA-104 Cell Line Associated With the Pathogenesis of Bovine Rotavirus Strain Circulated in Chinese Calves

Regulation of Viral Restriction by Post-Translational Modifications

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