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Department of Microbiology and Immunology

Zihai Li, MD, PhD

Dr. Zihai LiChairman and Professor
Department of Microbiology & Immunology

Program Leader
Cancer Immunology Program
Hollings Cancer Center
Medical University of South Carolina (MUSC)

Dr. Li received his medical degree from Henan Medical University and Peking Union Medical College, and his Ph.D. in immunology at Mount Sinai School of Medicine. He did his residency training in internal medicine at Montefiore Medical Center of the Albert Einstein College of Medicine, and completed his fellowship in medical oncology at Fred Hutchinson Cancer Research Center/University of Washington, Seattle.   

[Zihai Li lab home page]

Contact Info
Phone: (843) 792-1034
Office: HO-612F

Research Interests

Our laboratory is primarily interested in the mechanism of immune regulation by innate immunity in the context of tumors, infections and autoimmune diseases. By understanding how the immune system deals with microbes, tumors and self, we aim to design effective vaccines and therapeutics against cancer and infectious diseases. Presently our study focuses on two classes of proteins: heat shock proteins (HSPs) and Toll-like receptors (TLRs), both of which have been implicated as master regulators of immunity. We and others have discovered that the function of TLRs is dependent on the integrity of the HSP gp96 (or grp94) in the endoplasmic reticulum. Furthermore, depending on its expression level and its subcellular localization, gp96 can initiate systemic autoimmune disease as well as tumor-specific immunity, both of which have a significant clinical relevance. Using a combination of genetic, cell biological, biochemical and immunological tools, we aim to pinpoint the precise mechanism of TLR-gp96 interaction and define the functions of gp96 in hematopoiesis and in the functions of various cellular components in the immune system. In addition, since gp96 is also an important molecule in mediating the unfolded protein response (UPR), works are ongoing to dissect the roles of gp96 in organ development and oncogenesis, and to develop gp96-specific inhibitors for the treatment of diseases with a heavy pathogenic component of inflammation and metabolic dysregulation. Our study has a broad implication in understanding how the immune system operates physiologically and during pathological conditions, in light of the critical roles of TLRs and the UPR in the evolution, function and regulation of the immune response.

We take pride in sharing our expertise with trainees at all levels including graduate students, medical residents, clinical fellows and postdoctoral fellows. Trainees are expected to be original and hardworking, independent and interactive. They are encouraged to choose projects under the general conceptual frame as outlined above and are expected to function at a high level.

We are always seeking exceptionally motivated students and postdoctoral fellows to share our passion in research. Send your CV and description of your research interests to Dr. Li (

Recent Publications |Additional Publications

Rachidi S, Sun S, Wu BX, Jones E,  Drake RR, Ogretmen B, Cowart LA, Clarke CJ, Hannun YA, Chiosos G, Liu B,  Li Z (2015) Endoplasmic Reticulum Heat Shock Protein gp96 Maintains Liver Homeostasis and Promotes Hepatocellular Carcinogenesis . J Hepatol Apr 62 (4):879-88. [pdf]

Zhang Y, Wu BX, Metelli A, Thaxton JE, Hong F, Rachidi S, Ansa-Addo E, Sun S, Vasu C, Yang Y, Liu B, Li Z (2015) GP96 is a GARP Chaperone and Controls Regulatory T Cell Functions. J Clin Invest Feb 2;125 (2):859-69. [pdf]

Zhang J, Fu S, Sun S, Li Z Guo B (2014)  Inflammasome Activation has an Important Role in the Development of Spontaneous Colitis. Mucosal Immunology 29 January [pdf]

Thaxton JE, Liu B, Zheng P, Liu Y, Li Z (2014) Deletion of CD 24 Impairs Development of Heat Shock Protein gp96-Driven Autoimmune Disease Through Expansion of Myeloid-Derived Supressor Cells.  J Immunol  Jun 15;192(12):5679-86. [pdf]

Morales C, Rachidi S, Hong F, Sun S, Ouyang X, Wallace C, Zhang Y, Garret-Mayer E, Wu J, Liu B, Li Z (2014) Immune Chaperone gp96 Drives the Contribuitons of Macrophages to Inflammatory Colon Tumorigenesis. Cancer Res 74(2):446-59. [pdf]

Zhang Y, Helke KL, Coelho SG, Valencia JC, Hearing VJ, Sun S, Liu B, Li Z (2014) Essential Role of the Molecular Chaperone gp96 in Regulating Melanogenesis. Pigment Cell Melanoma Res. 27(1):82-9. [pdf]

Liu G, Lu S, Wang X, Page ST, Plymate SR, Higano CS, Zhang X, Greenberg NM, Li Z and Wu JD (2013) Soluble NKG2D Ligand Perturbs NK cell Peripheral Homeostasis and Accelerates Progression of Prostate Carcinoma. J Clin Invest. 123(10):4410-4422. [pdf]

Liu B, Staron M, Hong F, Wu BX, Sun S, Morales C, Crosson CE, Tomlinson S, Kim I, D Wu, Li Z (2013) Essential Roles of grp94 in Gut Homeostasis via Chaperoning Canonical Wnt Pathway. Proc Natl Acad Sci USA, 110(17):6877-82. [pdf]

Rachidi SM, Qin T, Sun S, Zheng JW, Li Z (2013) Molecular Profiling of Multiple Human Cancers defines an inflammatory cancer-associated molecular pattern and uncovers KPNA2 as a uniform poor prognostic marker. PLoS ONE, 8(3):e57911. [pdf]

An N, Lin YW, Mahajan S, Kellner JN, Wang Y, Li Z, Kraft AS, Kang Y (2013) Pim1 serine/threonine Kinase Regulates the Number and Functions of Murine Hematopoietic Stem Cells. Stem Cells, doi: 10.1002/stem.1369. [pdf]

Hong F, Liu B, Chiosis G, Gewirth DT and Li Z (2013) Αlpha 7 helix region of αlpha I domain is crucial for integrin binding to ER chaperone gp96: a potential therapeutic target for cancer metastasis. J Biol Chem, 288 (25):18243-8. [pdf]

Wu S, Dole K, Hong F, Noman AS, Isaacs J, Liu B, Li Z. (2012) gp96-independent inhibition of endotoxin response by chaperone-based peptide inhibitors. J Biol Chem. 287(24): 19896-903.  [pdf]

Wu S, Hong F, Gewirth D, Guo B, Liu B, Li Z. (2012) The molecular chaperone gp96/GRP94 interacts with Toll-like receptors and integrins via its C-terminal hydrophobic domain. J Biol Chem. 287(9):6735-42. [pdf]

Staron M, Wu S, Hong F, Stojanovic A, Du X, Bona R, Liu B, Li Z.(2011) Heat-shock protein gp96/grp94 is an essential chaperone for the platelet glycoprotein Ib-IX-V complex. Blood. 2011 Jun 30;117(26):7136-44. [pdf]

Audouard C, Le Masson F, Charry C, Li Z, Christians ES (2011) Oocyte–Targeted Deletion Reveals That Hsp90b1 Is Needed for the Completion of First Mitosis in Mouse Zygotes. PLoS ONE 6:2. 10.1371/journal.pone.0017109. [pdf]

Usmani S, Bona RD, Chiosis G and Li Z (2010) The anti-myeloma activity of a novel purine scaffold HSP90 inhibitor PU-H71 is via inhibition of both HSP90A and HSP90B1. J Hematol Oncol 3:40. doi:10.1186/1756-8722-3-40. [pdf]

Liu B, Yang Y, Qiu Z, Staron M, Hong F, Li Y, Wu S, Li Y, Hao B, Bona R, Han D, Li Z. (2010) Folding of Toll-like receptors by the HSP90 paralogue gp96 requires a substrate-specific cochaperone. Nature Commun. 2010 Sep;1(6):doi:10.1038/ncomms1070. [pdf]

Han JM, Kwon NH, Lee JY, Jeong SJ, Jung HJ, Kim HR, Li Z, Kim S (2010) Identification of gp96 as a novel target for treatment of autoimmune disease in mice. PLoS One 5(3):e9792. [pdf]

Staron M, Yang Y, Liu B, Li J, Shen Y, Zúñiga-Pflücker JC, Aguila HL, Goldschneider I, Li Z (2010) gp96, an endoplasmic reticulum master chaperone for integrins and Toll-like receptors, selectively regulates early T and B lymphopoiesis. Blood. 115(12):2380-90. [pdf]

Li Y, Zeng H, Xu RH, Liu B, Li Z (2009) Vaccination with human pluripotent stem cells generates a broad spectrum of immunological and clinical responses against colon cancer. Stem Cells 27(12):3103-11. [pdf]

Morales C, Wu S, Yang Y, Hao B, Li Z (2009) Drosophila glycoprotein 93 Is an ortholog of mammalian heat shock protein gp96 (grp94, HSP90b1, HSPC4) and retains disulfide bond-independent chaperone function for TLRs and integrins. J Immunol 183(8):5121-8. [pdf]

Liu B, Li Z (2008) Endoplasmic reticulum HSP90b1 (gp96, grp94) optimizes B-cell function via chaperoning integrin and TLR but not immunoglobulin. Blood 112(4):1223-30. [pdf]

Qiao Y, Liu B, Li Z (2008) Activation of NK cells by extracellular heat shock protein 70 through induction of NKG2D ligands on dendritic cells. Cancer Immun 8:12. [pdf]

Yang Y, Liu B, Dai J, Srivastava PK, Zammit DJ, Lefrancois L, Li Z (2007) Heat shock protein gp96 is a master chaperone for Toll-like receptors and is important in the innate function of macrophages. Immunity 26(2):215-26. [pdf]

Dai J, Liu B, Ngoi SM, Sun S, Vella AT, Li Z (2007) TLR4 Hyperresponsiveness via cell surface expression of heat shock protein gp96 potentiates suppressive function of regulatory T cells. J Immunol 178(5):3219-25. [pdf]

Dai J, Liu B, Cua DJ, Li Z (2007) Essential roles of IL-12 and dendritic cells but not IL-23 and macrophages in lupus-like diseases initiated by cell surface HSP gp96. Eur J Immunol 37(3):706-715. [pdf]

Liu B, Yang Y, Dai J, Medzhitov R, Freudenberg MA, Zhang PL, Li Z. (2006) TLR4 up-regulation at protein or gene level is pathogenic for lupus-like autoimmune disease. J Immunol 177(10):6880-8. [pdf]

Li Z, Qiao Y, Liu B, Laska EJ, et al. (2005) Combination of imatinib mesylate with autologous leukocyte-derived heat shock protein 70 and chronic myelogenous leukemia. Clin Cancer Res 11(12):4460-8.[pdf]

Yang Y, Li Z (2005) Roles of heat shock protein gp96 in the ER quality control: redundant or unique function? Mol Cells 20(2):173-82. [pdf]

Zheng H and Li Z (2004) Cutting Edge: Cross-presentation of cell-associated antigens to MHC class I molecule is regulated by a major transcription factor for molecular chaperones. J Immunol 173(10):5929-33. [pdf]

Millar DG, Garza KM, Odermatt B, Elford AR, Li Z and Ohashi PS (2003) Hsp70 promotes antigen presenting cell function and converts T cell tolerance to autoimmunity in vivo. Nat Med 9(12):1469 –1476. [pdf]

Liu B, Dai J, Zheng H, Stoilova D, Sun S and Li Z (2003) Cell surface expression of an endoplasmic reticulum resident heat shock protein gp96 triggers MyD88-dependent systemic autoimmune diseases. Proc Natl Acad Sci USA 100:15824-15829. [pdf]

Dai J, Liu B, Caudill MM, Zheng H, Qiao Y, Podack E AND Li Z (2003) Cell surface expression of heat shock protein gp96 enhances cross-presentation of cellular antigens and the generation of tumor-specific T cell memory. Cancer Immun 3:1-11. [pdf]

Li Z, Dai J, Zheng H, Liu B and Caudill M (2002) An integrated view of the roles and mechanisms of heat shock protein gp96-peptide complex in eliciting immune response. Front Biosci 7:731-751. [pdf]

Li Z, Menoret A and Srivastava PK (2002) Roles of heat shock proteins in antigen presentation and cross-presentation. Curr Opin Immunol 14:45-51. [pdf]

Zheng H, Dai J, Stoilova D and Li Z (2001) Surface targeting of an intracellular heat shock protein gp96 induces dendritic cell maturation and anti-tumor immunity. J Immunol 167:6731-6735. [pdf]

Caudill M and Li Z (2001) HSPPC-96: a personalized cancer vaccine. Exp Opin Bio Ther 1(3):539-548. [pdf]

Research Support

Title:  Endoplasmic Reticulum Chaperones in Cancer Biology and Therapy   
Agency: NCI, NIH (P01CA186866)
Role: PI

Funding Period: 9/01/2015 – 8/31/2020

Title: Thrombocytes in Cancer Immunity
Agency: NCI, NIH (1R01CA188419)
Role: PI
Funding Period: 4/01/2015 – 4/1/2020

Title: Chaperone Mechanisms in Innate Immunity
Agency: NIAID, NIH (2R01AI070603)
Role: PI
Funding Period: 4/01/2007 – 5/31/2017

Title: Cancer Support Grant for Hollings Cancer Center
Agency: NCI, NIH (5P30CA138313)
Role: Program Leader of the Cancer Immunology Program (PI Dr. Andrew Kraft)
Funding Period: 04/01/2009-08/31/2019

Title: Plerixafor for myeloablative allogenic hematopoietic stem cell transplantation
Agency: NHLBI,NIH (1K08HL 103780-01A1)
Role: Co-mentor (PI: Dr. Yubin Kang)
Funding Period: 09/05/2011 – 09/04/2016

Title: MUSC/HCC Paul Calabresi Clinical Oncology Training Program Plan
Agency: NCI/NIH (1 K12 CA157688-01A1)
Role: Member of the Curriculum Subcommittee (PIs: Drs. Andrew Kraft and Michael Lilly)
Funding Period: 04/01/2013 – 03/31/2018

Title: South Carolina Center of Economic Excellence Endowed Program in Stem Cell Research
Agency: State of South Carolina USA
Role: PI
Funding Period: 07/2010-ongoing commitment

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