About Us
The Zheng Lab at the University of Illinois Chicago focuses on understanding how viruses interact with host cells, particularly in the context of viral entry and replication. Our research delves into the mechanisms by which class I viral fusion proteins, such as those from HIV-1, Ebola virus, and SARS-CoV-2, are processed and regulated within host cells. We investigate host factors like ER chaperones, ubiquitin ligases, and restriction factors that influence viral protein maturation and degradation. Additionally, our studies explore the role of cellular receptors and pathways, such as NPC1-mediated endocytosis, in facilitating or restricting viral entry. Through these investigations, we aim to uncover potential antiviral targets and contribute to the development of effective therapeutic strategies
Meet Dr. Zheng
Class I Fusion Protein Biosynthesis and Inhibition
HIV-1, influenza virus, Ebola virus, and SARS-CoV-2 produce class I fusion proteins to infect cells. The core structure of class I fusion proteins features trimeric hairpins with a central coiled-coil structure, which are produced from their polypeptide precursors after cleavage by furin. During this process, class I fusion proteins are targeted by different types of host factors. Currently, we are investigating how ER chaperones (calnexin, calreticulin, PDIA3) and class I α-mannosidases (such as MAN1B1) trigger class I fusion protein degradation via reticulophagy. In addition, we are investigating how MARCHF E3 ubiquitin ligases inhibit furin to block their maturation. Moreover, we are investigating how SERINC5 inactivates them and how SERINC5 is counteracted by HIV-1 Nef, MLV glycoGag, and EIAV S2 proteins. On the other hand, we are also investigating in addition to ACE2, TMPRSS2, and CTSL, how SARS-CoV-2 enters cells via Niemann-Pick C1 (NPC1) known as the Ebola virus receptor. These investigations will lead to broad antiviral mechanisms to inhibit these highly pathogenic human viruses.
Our Projects
Class I fusion protein degradation by reticulophagy
The precursors of class I fusion proteins are synthesized in the ER, where they receive initial N-glycosylation and undergo protein folding and trimerization. However, the majority of these viral proteins are misfolded, and the elevation of misfolded proteins not only induces ER stress but also triggers their degradation by different mechanisms. We reported that these viral glycoproteins are new clients for class I α-mannosidases such as MAN1B1, which select substrates for ER-associated protein degradation (ERAD). We also reported that ER chaperones such as calnexin, calreticulin, and PDIA3 target Ebola virus glycoproteins to reticulophagy via K27-polyubiquitination. Currently, we are investigating the molecular mechanisms of how reticulophagy selectively targets these viral glycoproteins.
Inhibition of class I fusion maturation by MARCHF
Properly folded class I fusion proproteins exit the ER and enter the Golgi to undergo maturation. High-mannose type N-glycans are processed into complex-type and hybrid-type N-glycans, and O-glycans are further added to these proteins. Furin further cleaves these proproteins into the surface receptor-binding and the transmembrane fusion subunits. We reported that after removal of the prodomain, furin is subjected to K33-polyubiquitination by MARCHF2, MARCHF8, and MARCHF9 to egress the TGN, which is counteracted by USP32. Polyubiquitinated furin undergoes exocytosis via exosomes, where it is cleaved by an unknown cellular protease for shedding, producing extracellularly active fuin. Polyubiquitinated furin also migrates to the cell surface, which is phosphorylated by CKII for endocytosis. Phosphorylated furin undergoes retrograde transport from early endosomes to late endosomes, where it binds PACS1 and is retrieved to the TGN by AP1 and Rab9. Furin is also dephosphorylated by PP2A, which directly retrieves furin from early endosomes to the TGN. Retrieved furin is re-targeted by M2, M8, and M9 for the next round of cycling. Alternatively, furin is activated by another unknown cellular protease in the TGN to produce intracellularly active furin that processes proproteins such as class I fusion proteins for maturation.
SERINC5 antiviral mechanism and viral antagonism
Serine incorporator 5 (SERINC5) is a multipath transmembrane host restriction factor, which is incorporated into virions from the plasma membrane and inhibits viral entry. This SERINC5 activity is antagonized by different retroviral accessory proteins including HIV-1 Nef, MLV glycoGag, and EIAV S2. We reported that SERINC5 disrupts HIV-1 Env trimer formation to inactivate the Env activity, and these accessory proteins degrade SERINC5 via the endocytic pathway. However, the precise SERINC5 antiviral mechanism and the viral antagonism are still unclear. Currently, we are investigating how SERINC5 travels to the cell surface from the TGN for incorporation. We reported that SERINC5 undergoes K33-polyubiquitination by Cul3/KLHL20 E3 ubiquitin ligase, which is required for its post-Golgi trafficking. We are also investigating how SERINC5 is internalized from the plasma membrane, which excludes SERINC5 from incorporation into virions. We reported that SERINC5 is phosphorylated by CCNK/CDK13, which is required for its endocytic degradation by Nef. We will continue to address these outstanding questions to elucidate the important role of SERINC5 in retroviral infection.
SARS-CoV-2 entry mechanism
SARS-CoV-2 entry requires not only the cell surface receptor ACE2, but also two cellular proteases TMPRSS2 and CTSL to further cleave its spike proteins on the cell surface or in late endosomes. However, the precise entry mechanism still needs to be elucidated. Recently, we reported the identification of Tubeimosides as potent Ebola virus entry inhibitors by targeting its receptor NPC1 from screening a natural compound library. Surprisingly, we found that Tubeimosides also inhibit SARS-CoV-2 entry at the same potency, which led us to investigate the role of NPC1 in SARS-CoV-2 entry. After knocking out NPC1 by CRISPR/Cas9, we found that NPC1 is required for SARS-CoV-2 entry and infection in both TMPRSS2(-) and TMPRSS(+) cells. These results demonstrate that the endocytic entry route plays a predominant role in SARS-CoV-2 infection. Currently, we are investigating how SARS-CoV-2 spike proteins interact with NPC1 and how NPC1 triggers the membrane fusion in late endosomes for infection.
Our Members
Our Publications
Publication list
- 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. BioRxiv, 2025, doi: https://doi.org/10.1101/2025.03.06.641798.
- 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 Proteins (MARCHF) and Ubiquitin-Specific Protease 32 (USP32) via Nondegradable K33-Polyubiquitination. Adv Sci (Weinh) 2024 Jul 19; 11(35):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.
- 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.
- 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.
- 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.
- 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).
- 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).
- 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).
- 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.
- 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