The Emerging Role of the Serine Incorporator Protein Family in Regulating Viral Infection

Abstract

Serine incorporator (SERINC) proteins 1-5 (SERINC1-5) are involved in the progression of several diseases. SERINC2-4 are carrier proteins that incorporate the polar amino acid serine into membranes to facilitate the synthesis of phosphatidylserine and sphingolipids. SERINC genes are also differentially expressed in tumors. Abnormal expression of SERINC proteins occurs in human cancers of the breast, lung, colon, liver, and various glands, as well as in mouse testes. SERINC proteins also affect cleft lip and palate and nerve-related diseases, such as seizure Parkinsonism and borderline personality. Moreover, SERINC proteins have garnered significant interest as retroviral restriction factors, spurring efforts to define their function and elucidate the mechanisms through which they operate when associated with viruses. Human SERINC proteins possess antiviral potential against human immunodeficiency virus (HIV), SARS-COV-2, murine leukemia virus (MLV), equine infectious anemia virus (EIAV), and hepatitis B virus (HBV). Furthermore, the crystal structure is known, and the critical residues of SERINC5 that act against HIV have been identified. In this review, we discuss the most prevalent mechanisms by which SERINC3 and SERINC5 antagonize viruses and focus on the potential therapeutic applications of SERINC5/3 against HIV.

Keywords: COVID-19; DNA virus; HIV; SERINC; influenza virus; retroviral virus.

FIGURE 1

The phylogenetic relationships between humans and other commonly used experimental animals are depicted using MEGA7 software. Maximum likelihood was chosen as the statistical method. The bootstrap value was set to 1,000 gaps/missing data treatment is complete deletion. (Created by Biorender.com).

FIGURE 2

Summary of SERINC-related diseases in human and animal models. Virus-related diseases include acquired immunodeficiency syndrome (HIV; SERINC1, 3, 4, 5), influenza-pseudotyped particles (SERINC5), COVID-19 (SERINC2, 3), and viral hepatitis type B (HBV) (SERINC5). Nerve-related diseases include seizure Parkinsonism (SERINC1, 2), autism spectrum disorder (SERINC2), borderline personality (SERINC5), and alcohol dependence (SERINC2). Cancer types include lung cancer (non-small cell lung cancer and lung adenocarcinoma; SERINC1, 2), liver cancer (SERINC1), colorectal tumor (SERINC3), and melanoma (SERINC3), among others. Animal models include rabies virus (RABV), testicular tumor, and nonobese diabetes. Cleft lip/palate is associated with SERINC1. (Created by Biorender.com).

FIGURE 3

The role of SERINC5 in HIV infection. (A) HIV infects cells and antagonizes SERINC5. (B) SERINC5 inhibits viral infection. SERINC5 proteins are normally localized in the plasma membrane of the cell. Upon viral infection, Nef forms complexes with CycK and CDK13, combining with SERINC5 to target SERINC5 to endosomes and lysosomes for destruction. During HIV budding, an N-glycosylated and high-molecular-weight form of SERINC5 preferentially integrates into virions. If viruses carrying SERINC5 infect other cells, the packaged SERINC5 will exert several antiviral activities. SERINC5 can interfere with Env activity and prevent Env folding, reducing the fusion between cells. SERINC5 increases the expression of TIM1 and enhances the inhibition of Tim on HIV. SERINC5 becomes internalized and translocates to the mitochondrial membrane, where it is associated with MAVS and TRAF6, resulting in MAVS aggregation and polyubiquitylation of TRAF6. MVAS recognizes viral MDA5 and RIG-I, enhancing the expression of genes encoding type I interferons (IFNs) and nuclear factor κB (NF-κB) signaling. MDA5, melanoma differentiation gene 5; RIG-I, retinoic acid-inducible gene I; Cyck, cyclin K; CDK13, cyclin-dependent kinase 13. (Created by Biorender.com).

FIGURE 4

Targeting strategies against HIV by regulating SERINC5/3. (A), CRISPER/Cas9 gene editing can be used to overexpress SERINC5/3 to increase the differentiation of human-induced pluripotent stem cells (iPSCs) into different immune cells, such as T cells and macrophages. SERINC5/3 was overexpressed in CD4⁺ T cells, and these immune cells can eliminate HIV loads. (B), To activate SERINC5/3 modification activity or increase the protein expression of SERINC5/3 to defend against HIV, active materials, such as monomers in Chinese herbal medicine, small molecules, and peptides should be selected and their activity confirmed. Using the crystal structure of virus binding to the SERINCs, additional drugs from molecular libraries can be found by virtual screening. To efficiently deliver the selected drugs or peptides, nanoparticles should be considered as a carrier. (Created by Biorender.com).