Donghai Wang

Overview:

Inflammation underlies a variety of human diseases such as obesity, diabetes, cardiovascular diseases, neurodegenerative diseases, arthritis and cancer. Together, these diseases constitute a major challenge to the well being of modern human society. Understanding the fundamental mechanisms of inflammation may provide rationales for designing novel interventions to treat these maladies. Autoinflammatory diseases are an emerging family of illness, characterized by dysregulation of innate immune responses. Studies of these hereditary human disorders have provided invaluable insight into basic cellular and molecular mechanisms of the innate immune responses and have contributed significantly to the development of targeted therapies for common human inflammatory diseases such as arthritis. My long term goal is to understand the pathophysiological mechanisms of autoinflammatory diseases and to apply knowledge from such studies to develop novel treatment of inflammatory human diseases. Our recent studies of one of such diseases, namely mevalonate kinase deficiency, has allowed us to unravel the unexpected connection between the cholesterol-biosynthesis mevalonate pathway and toll like receptor (TLR)-mediated phosphatidyl inosital 3(PI3)-kinase signaling. These exciting new discoveries will greatly advance our knowledge of innate immune signaling and may provide clues for new interventions of a variety of human diseases.

Positions:

Assistant Professor in Medicine

Medicine, Rheumatology and Immunology
School of Medicine

Assistant Professor in Immunology

Immunology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 2004

Sun Yat Sen University (China)

Grants:

Innate Immune Inhibition of the Mevalonate Pathway impairs Neurodevelopment during ZIKv infection

Administered By
Medicine, Rheumatology and Immunology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Censoring Inflammation by Protein Geranylgeranylation

Administered By
Medicine, Rheumatology and Immunology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Regulation of Inflammation by the Mevalonate Pathway in Mouse Model of RA

Administered By
Medicine, Rheumatology and Immunology
Awarded By
Arthritis Foundation
Role
Principal Investigator
Start Date
End Date

APCs and environmental cues for inflammation-linked Th17 immunity

Administered By
Immunology
Awarded By
National Institutes of Health
Role
Collaborator
Start Date
End Date

APCs and environmental cues for inflammation-linked Th17 immunity

Administered By
Immunology
Awarded By
National Institutes of Health
Role
Collaborator
Start Date
End Date

Publications:

Protein prenylation restrains innate immunity by inhibiting Rac1 effector interactions.

Rho family proteins are prenylated by geranylgeranyltransferase type I (GGTase-I), which normally target proteins to membranes for GTP-loading. However, conditional deletion of GGTase-I in mouse macrophages increases GTP-loading of Rho proteins, leading to enhanced inflammatory responses and severe rheumatoid arthritis. Here we show that heterozygous deletion of the Rho family gene Rac1, but not Rhoa and Cdc42, reverses inflammation and arthritis in GGTase-I-deficient mice. Non-prenylated Rac1 has a high affinity for the adaptor protein Ras GTPase-activating-like protein 1 (Iqgap1), which facilitates both GTP exchange and ubiquitination-mediated degradation of Rac1. Consistently, inactivating Iqgap1 normalizes Rac1 GTP-loading, and reduces inflammation and arthritis in GGTase-I-deficient mice, as well as prevents statins from increasing Rac1 GTP-loading and cytokine production in macrophages. We conclude that blocking prenylation stimulates Rac1 effector interactions and unleashes proinflammatory signaling. Our results thus suggest that prenylation normally restrains innate immune responses by preventing Rac1 effector interactions.
Authors
Akula, MK; Ibrahim, MX; Ivarsson, EG; Khan, OM; Kumar, IT; Erlandsson, M; Karlsson, C; Xu, X; Brisslert, M; Brakebusch, C; Wang, D; Bokarewa, M; Sayin, VI; Bergo, MO
MLA Citation
Akula, Murali K., et al. “Protein prenylation restrains innate immunity by inhibiting Rac1 effector interactions.Nat Commun, vol. 10, no. 1, Sept. 2019, p. 3975. Pubmed, doi:10.1038/s41467-019-11606-x.
URI
https://scholars.duke.edu/individual/pub1410018
PMID
31484924
Source
pubmed
Published In
Nature Communications
Volume
10
Published Date
Start Page
3975
DOI
10.1038/s41467-019-11606-x

Sox4 Is Required for the Survival of Pro-B Cells

Authors
URI
https://scholars.duke.edu/individual/pub1117107
Source
manual

Malaria-Induced NLRP12/NLRP3-Dependent Caspase-1 Activation Mediates Inflammation and Hypersensitivity to Bacterial Superinfection

Authors
URI
https://scholars.duke.edu/individual/pub1117108
Source
manual

CARMA3 deficiency abrogates G protein-coupled receptor-induced Nf-kB activation

Authors
URI
https://scholars.duke.edu/individual/pub1117109
Source
manual

Control of antiviral innate immune response by protein geranylgeranylation.

The mitochondrial antiviral signaling protein (MAVS) orchestrates host antiviral innate immune response to RNA virus infection. However, how MAVS signaling is controlled to eradicate virus while preventing self-destructive inflammation remains obscure. Here, we show that protein geranylgeranylation, a posttranslational lipid modification of proteins, limits MAVS-mediated immune signaling by targeting Rho family small guanosine triphosphatase Rac1 into the mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) at the mitochondria-ER junction. Protein geranylgeranylation and subsequent palmitoylation promote Rac1 translocation into MAMs upon viral infection. MAM-localized Rac1 limits MAVS' interaction with E3 ligase Trim31 and hence inhibits MAVS ubiquitination, aggregation, and activation. Rac1 also facilitates the recruitment of caspase-8 and cFLIPL to the MAVS signalosome and the subsequent cleavage of Ripk1 that terminates MAVS signaling. Consistently, mice with myeloid deficiency of protein geranylgeranylation showed improved survival upon influenza A virus infection. Our work revealed a critical role of protein geranylgeranylation in regulating antiviral innate immune response.
Authors
Yang, S; Harding, AT; Sweeney, C; Miao, D; Swan, G; Zhou, C; Jiang, Z; Fitzgerald, KA; Hammer, G; Bergo, MO; Kroh, HK; Lacy, DB; Sun, C; Glogauer, M; Que, LG; Heaton, NS; Wang, D
MLA Citation
Yang, Shigao, et al. “Control of antiviral innate immune response by protein geranylgeranylation.Sci Adv, vol. 5, no. 5, May 2019, p. eaav7999. Pubmed, doi:10.1126/sciadv.aav7999.
URI
https://scholars.duke.edu/individual/pub1386935
PMID
31149635
Source
pubmed
Published In
Science Advances
Volume
5
Published Date
Start Page
eaav7999
DOI
10.1126/sciadv.aav7999