Decoding viral entry and host restrictions to uncover novel antiviral mechanisms
Research Overview
The Zheng Lab investigates how enveloped viruses—including HIV-1, Ebola virus, SARS-CoV-2, and influenza virus—enter host cells and how cellular defense mechanisms restrict infection. By dissecting the interplay between viral fusion proteins and host pathways such as ER quality control, ubiquitination, and endosomal trafficking, we aim to uncover conserved antiviral targets and enable the development of broad-spectrum therapeutics.
Our Projects
Class I fusion protein degradation by reticulophagy
HIV-1, SARS-CoV-2, Ebola virus, and influenza A virus rely on class I fusion glycoproteins for entry and productive infection. These proteins are synthesized through the host secretory pathway, where multiple host factors act to restrict their expression, maturation, and trafficking.
In the endoplasmic reticulum (ER), chaperones such as calnexin, calreticulin, and PDIA3 may target these viral glycoproteins for degradation via ER-phagy, a process dependent on the ER-phagy receptor FAM134B isoform 2/RETREG1-2. We also identified Membralin (TMEM259) as a noncanonical ER-phagy receptor that broadly targets class I fusion proteins by coordinating glycoprotein recognition via mannosidase MAN1B1.
At the Golgi, membrane-associated RING-CH (MARCH) E3 ligases 2, 8, and 9 re-direct furin to the exosome pathway, which inhibits the furin-mediated cleavage and results in defective maturation.
Together, these findings reveal multilayered host quality-control mechanisms in the ER and Golgi that limit viral glycoprotein function and suppress infection.
Inhibition of class I fusion maturation by MARCHF
Enveloped viruses such as HIV-1, Ebola virus, influenza A virus, and SARS-CoV-2 enter cells through membrane fusion at either the plasma membrane or within endosomes. Unlike others, SARS-CoV-2 uses both routes—via ACE2 and TMPRSS2 at the cell surface or through cathepsin-dependent activation in endosomes—raising the question of how its spike protein remains fusion-competent during trafficking.
We identified Niemann–Pick C1 (NPC1) as an essential intracellular receptor that enables spike-mediated fusion in acidic late endosomes and lysosomes. Under low pH, NPC1 binds the spike protein through a site distinct from ACE2, facilitating a receptor switch that promotes endosomal entry. This pathway is particularly important for variants such as Omicron, which preferentially utilize endosomal fusion.
These findings uncover a pH-dependent ACE2-to-NPC1 receptor switch that expands the understanding of coronavirus entry. Ongoing work aims to define conserved host factors regulating endosomal entry across SARS-CoV-2, Ebola virus, and influenza A virus.
Vpr
HIV-1 Vpr is a multifunctional accessory protein that modulates host nuclear transport, ubiquitin signaling, and innate immunity. Through the DCAF1–Cullin4 E3 ligase complex, Vpr remodels the host proteome, induces G2/M cell cycle arrest, and suppresses innate immune activation by blocking nuclear import of key transcription factors such as IRF3 and NF-κB.
Despite these roles, the mechanisms by which Vpr enhances replication remain incompletely understood. Using Vpr-dependent HIV-1 replication systems in CD4⁺ T cells, we and others have found that Vpr is required for efficient expression of the viral envelope glycoprotein (Env), suggesting that it counteracts an unidentified host restriction factor that limits Env biogenesis.
These findings point to a previously unrecognized pathway by which Vpr promotes HIV-1 replication and highlight new directions for identifying host factors that restrict viral protein expression.
Nef
HIV-1 Nef is a conserved accessory protein essential for viral replication, in part by counteracting host restriction factors that inhibit infectivity. One such factor is SERINC5, which is ubiquitinated by the Cullin3–KLHL20 E3 ligase complex in the trans-Golgi network and incorporated into virions to block viral entry. Nef antagonizes SERINC5 by inducing its phosphorylation via Cyclin K–CDK13, leading to endocytosis and lysosomal degradation.
However, SERINC5 primarily restricts laboratory-adapted HIV-1 strains, suggesting additional restriction mechanisms. We identified ADAM17 as a second Nef-targeted factor that retains the viral envelope glycoprotein (Env) in the endoplasmic reticulum (ER), preventing its maturation. Nef counteracts this by promoting exosome-mediated secretion of ADAM17, restoring Env processing and viral infectivity.
These findings reveal that Nef enhances HIV-1 replication by neutralizing multiple host restriction pathways that target both viral entry and glycoprotein maturation.
Principal Investigator
Visiting Scholars
Graduate Members
Undergraduate Members
Alumni
Here are our past members:
Rokeya Pervin, Ph.D, Postdoc
Feridoon Najamabadi, Ph.D, Research Scientist
Steve Jo, Ph.D, Research Scientist
Wen Luo, MD/Ph.D, Visiting Scholar
Vincent Sanchez, Undergraduate Researcher
Florina Carrillo, Undergraduate Researcher
Aksha Vahora, Undergraduate Researcher
Karylle Baltazar, Undergraduate Researcher
Our Publications
Publication list
2026
Camilleri JM, Zhang J, Wang T, Li S, Zheng YH. TMEM259/MEMBRALIN is a non-canonical ER-phagy receptor that associates with MAN1B1 and VCP to eliminate viral glycoproteins. Autophagy Rep. 2026 5(1):2639256.
Camilleri JM, Ahmad I, Zhang J, Li S, Zheng YH. RETREG1/FAM134B-mediated micro-ER-phagy in the retrovirus–SERINC5 arms race. Autophagy Rep. 2026 5(1):2602971.
2025
Zhang J, Lu X, Li S, Wang T, Ahmad I, Zheng YH. Membralin Assembles a MAN1B1–VCP Complex to Target Foreign Glycoproteins from the Endoplasmic Reticulum to Lysosomes for Degradation. Adv Sci (Weinh). 2025 13:e19256.
Ahmad I, Zhang J, Li R, Su W, Liu W, Wu Y, Khan I, Liu X, Li LF, Li S, Zheng YH. Murine leukemia virus glycoGag antagonizes SERINC5 via ER-phagy receptor RETREG1. PLoS Pathogens. 2024 21(10):e1013023.
2024
Su W, Ahmad I, Wu Y, Tang L, Khan I, Ye B, Liang J, Li S, Zheng YH. Furin Egress from the TGN is Regulated by Membrane‐Associated RING‐CH Finger (MARCHF) Proteins and Ubiquitin‐Specific Protease 32 (USP32) via Nondegradable K33‐Polyubiquitination. Adv Sci (Weinh). 2024 Jul 19; 11:e2403732.
Khan I, Li S, Tao L, Wang C, Ye B, Li H, Liu X, Ahmad I, Su W, Zhong G, Wen Z, Wang J, Hua RH, Ma A, Liang J, Wan XP, Bu ZG, Zheng YH. Tubeimosides are pan-coronavirus and filovirus inhibitors that can block their fusion protein binding to Niemann-Pick C1. Nat Commun. 2024 Jan 2;15(1):162.
2023
Zhang J, Wang B, Gao X, Peng C, Shan C, Johnson SF, Schwartz RC, Zheng YH. RNF185 regulates proteostasis in Ebolavirus infection by crosstalk between the calnexin cycle, ERAD, and reticulophagy. Nat Commun. 2022 Oct 12;13(1):6007.
2022
Wang B, Zhang J, Liu X, Chai Q, Lu X, Yao X, Yang Z, Sun L, Johnson SF, Schwartz RC, Zheng YH. Protein disulfide isomerases (PDIs) negatively regulate ebolavirus structural glycoprotein expression in the endoplasmic reticulum (ER) via the autophagy-lysosomal pathway. Autophagy. 2022 Oct;18(10):2350-2367.
Li S, Li R, Ahmad I, Liu X, Johnson SF, Sun L, Zheng YH. Cul3-KLHL20 E3 ubiquitin ligase plays a key role in the arms race between HIV-1 Nef and host SERINC5 restriction. Nat Commun. 2022 Apr 26;13(1):2242.
2021
Chai Q, Li S, Collins MK, Li R, Ahmad I, Johnson SF, Frabutt DA, Yang Z, Shen X, Sun L, Hu J, Hultquist JF, Peterlin BM, Zheng YH. HIV-1 Nef interacts with the cyclin K/CDK13 complex to antagonize SERINC5 for optimal viral infectivity. Cell Rep. 2021 Aug 10;36(6):109514.
2020
Qiu X, Eke IE, Johnson SF, Ding C, Zheng YH. Proteasomal degradation of human SERINC4: A potent host anti-HIV-1 factor that is antagonized by nef. Curr Res Virol Sci. 2020;1.
Yu C, Li S, Zhang X, Khan I, Ahmad I, Zhou Y, Li S, Shi J, Wang Y, Zheng YH. MARCH8 Inhibits Ebola Virus Glycoprotein, Human Immunodeficiency Virus Type 1 Envelope Glycoprotein, and Avian Influenza Virus H5N1 Hemagglutinin Maturation. mBio. 2020 Sep 15;11(5).
2019
Zhang X, Shi J, Qiu X, Chai Q, Frabutt DA, Schwartz RC, Zheng YH. CD4 Expression and Env Conformation Are Critical for HIV-1 Restriction by SERINC5. J Virol. 2019 Jul 15;93(14).
Ahmad I, Li S, Li R, Chai Q, Zhang L, Wang B, Yu C, Zheng YH. The retroviral accessory proteins S2, Nef, and glycoMA use similar mechanisms for antagonizing the host restriction factor SERINC5. J Biol Chem. 2019 Apr 26;294(17):7013-7024.
Li S, Ahmad I, Shi J, Wang B, Yu C, Zhang L, Zheng YH. Murine Leukemia Virus Glycosylated Gag Reduces Murine SERINC5 Protein Expression at Steady-State Levels via the Endosome/Lysosome Pathway to Counteract SERINC5 Antiretroviral Activity. J Virol. 2019 Jan 15;93(2).
Shi J, Xiong R, Zhou T, Su P, Zhang X, Qiu X, Li H, Li S, Yu C, Wang B, Ding C, Smithgall TE, Zheng YH. HIV-1 Nef Antagonizes SERINC5 Restriction by Downregulation of SERINC5 via the Endosome/Lysosome System. J Virol. 2018 Jun 1;92(11).
2018
Frabutt DA, Wang B, Riaz S, Schwartz RC, Zheng YH. Innate Sensing of Influenza A Virus Hemagglutinin Glycoproteins by the Host Endoplasmic Reticulum (ER) Stress Pathway Triggers a Potent Antiviral Response via ER-Associated Protein Degradation. J Virol. 2018 Jan 1;92(1).
2017
Zhang X, Zhou T, Yang J, Lin Y, Shi J, Zhang X, Frabutt DA, Zeng X, Li S, Venta PJ, Zheng YH. Identification of SERINC5-001 as the Predominant Spliced Isoform for HIV-1 Restriction. J Virol. 2017 May 15;91(10).
Wang B, Wang Y, Frabutt DA, Zhang X, Yao X, Hu D, Zhang Z, Liu C, Zheng S, Xiang SH, Zheng YH. Mechanistic understanding of N-glycosylation in Ebola virus glycoprotein maturation and function. J Biol Chem. 2017 Apr 7;292(14):5860-5870.
2016
Frabutt DA, Zheng YH. Arms Race between Enveloped Viruses and the Host ERAD Machinery. Viruses. 2016 Sep 19;8(9).
Publications
Join Our Lab
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Post-Docs
We have multiple open positions to be filled soon. Please send your CV to Dr. Zheng.
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Graduate Students
We welcome students from GEMS and MSTP programs to join our lab to pursue a PhD or MD/PhD. Students from these programs who are interested in our research projects please directly contact Dr. Zheng via email.
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Undergraduates