# The role of SERINC5 in HIV-1 replication

> **NIH NIH R01** · MICHIGAN STATE UNIVERSITY · 2020 · $391,250

## Abstract

SERINC5 (Ser5) is a novel restriction factor that strongly blocks HIV-1 entry. Ser5 belongs to the serine
incorporator (SERINC) family that has five members (1 to 5). They are type III integral membrane proteins with
9-11 transmembrane domains. Ser5 and Ser3 were initially identified as the counteractive target of HIV-1 Nef
that increases viral infectivity. Although SERINC proteins share 31-58% sequence homology, only Ser5 and
Ser3 have antiviral activities, albeit the Ser3 activity is weak. In addition, although the Ser4 antiviral activity was
reported, it is poorly expressed at protein levels. Ser5 is antagonized by HIV-1 Nef as well as MLV glycoGag
and EIAV S2. The Nef antagonism of Ser5 plays an important role in the prevalence of primate lentiviruses in
their hosts. Thus, Ser5 is an important restriction factor for retroviruses. Our goal is to investigate the molecular
mechanisms of how Ser5 inhibits HIV-1 replication and conversely, how Ser5 is counteracted by Nef. First, we
will elucidate how Ser5 blocks HIV-1 entry. Ser5 is packaged into virions to block viral entry, but the mechanism
is still unclear. It is also unclear why the Ser5 inhibition depends on viral Env glycoproteins. Tier 1 viruses, which
are largely laboratory-adapted viruses, are very sensitive, whereas most Tier 2/3 viruses, which are the vast
majority of circulating strains, are resistant to Ser5. Notably, native Tier 1 Env trimers predominantly occupy an
open conformation, whereas those Tier 2/3 trimers occupy a closed conformation. In addition, Ser5 makes HIV-
1 become sensitive to neutralizing antibodies, suggesting that Ser5 may modify the Env conformation. We
hypothesize that Ser5 disrupts Env trimers in an open state, resulting in Env inactivation and blockade of HIV-1
entry. We will use a sensitive bimolecular fluorescence complementation (BiFC) assay to study Env
oligomerization and SERINC-Env interactions in live cells and use virologic assays to elucidate how HIV-1 entry
is blocked by Ser5 and also likely by Ser4. Second, We will elucidate how Nef antagonizes Ser5. Nef
counteracts Ser5 by downregulating Ser5 from plasma membrane and excluding it from virions, but the precise
mechanism is still unclear. We reported that Nef rapidly internalizes Ser5 via receptor-mediated endocytosis
and re-localizes Ser5 to endosomes. Ser5 is then targeted to lysosomes in a ubiquitination-dependent manner
for degradation. Cyclin K (CycK) is a previously identified Nef-binding protein that binds Cyclin-dependent kinase
(CDK) 12 and 13 and regulates gene expression and genome stability. We found that CycK and CDK13 are
required for Nef-downregulation of Ser5. We hypothesize that Nef recruits CDK13/CycK to plasma membrane
to phosphorylate Ser5 and targets Ser5 to endosome/lysosome pathways for degradation. We will study the
critical role of the CDK13/CycK complex in Nef downregulation of Ser5 by testing the Ser5 phosphorylation and
determine how the phosphorylation affects the Ser5 ...

## Key facts

- **NIH application ID:** 9974474
- **Project number:** 5R01AI145504-02
- **Recipient organization:** MICHIGAN STATE UNIVERSITY
- **Principal Investigator:** YONG-HUI ZHENG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $391,250
- **Award type:** 5
- **Project period:** 2019-07-08 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9974474

## Citation

> US National Institutes of Health, RePORTER application 9974474, The role of SERINC5 in HIV-1 replication (5R01AI145504-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9974474. Licensed CC0.

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