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

Abstract

The serine incorporator (SERINC) protein family has five paralogous members with 9-11 transmembrane domains. SERINC5 is a potent host restriction factor and antagonized by HIV-1 Nef and two other retroviral accessory proteins via the lysosomal degradation pathway. Here, we investigated human SERINC4 expression and antiviral mechanisms. Unlike its four paralogs, human SERINC4 is subjected to proteasome-mediated turnover, resulting in ~250-fold lower expression than SERINC5. However, when expression was normalized, human SERINC4 restricted HIV-1 replication as effectively as SERINC5, and SERINC4 was also antagonized by Nef via the lysosomal pathway. Although SERINC4 proteins are conserved within primates or rodents, their N-terminal regions are highly variable across species. Interestingly, unlike human SERINC4, murine SERINC4 was stably expressed but had a very poor antiviral activity. We created stable SERINC4 chimeras by replacing the N-terminal region and found that the 1-34 and 35-92 amino acids determine SERINC4 antiviral activity or protein expression, respectively. Using these chimeras, we demonstrate that SERINC4 is incorporated into HIV-1 virions and restricts Tier 1 HIV-1 more effectively than Tier 3 HIV-1. Importantly, SERINC4 increases HIV-1 sensitivity to broadly neutralizing antibodies. Thus, human SERINC4 strongly restricts HIV-1 replication when it is overexpressed, which reflects a potential antiviral activity of this gene product under physiological conditions.

From Beginning to End: Expanding the SERINC3 Interactome Through an in silico Analysis

“…For example, SERINC4 protein is subject to degradation by the proteasome, which contributes to its activity in restricting HIV-1 replication. 36 In addition, N -glycosylation of SERINC5 by has been observed to be preferentially incorporated into HIV-1 virions. 13 Our search for putative sites of posttranslational modifications in SERINC3 extra-membrane regions yielded the prediction of sites of putative phosphorylation, glycosylation, acetylation, and ubiquitination.…”

HIV-1 Nef interacts with the cyclin K/CDK13 complex to antagonize SERINC5 for optimal viral infectivity

“…SERINC5 and, to a lesser degree, SERINC3 are specifically targeted by Nef in order to increase HIV-1 infectivity (Rosa et al, 2015;Usami et al, 2015). SERINC4 also has a Nef-sensitive anti-HIV-1 activity, but it is rapidly turned over by the host cell proteasomes (Qiu et al, 2020).…”