Francis Ka-Ming Chan

Overview:

Our lab is interested in how cell death impacts innate inflammation and immune responses.  We have a long-standing interest in the biology and signaling mechanism of tumor necrosis factor (TNF), a key cytokine that regulates many inflammatory diseases (e.g. rheumatoid arthritis, inflammatory bowel diseases etc), pathogen infections, and cancer.  Several key discoveries made by the PI during his graduate school and postdoctoral training include identification of one of the first cell cycle inhibitors, INK4d-p19 (Mol Cell Biol. 1995, cited over 300 times), and the discovery of the "pre-ligand assembly domain (PLAD)" that mediates TNF receptors signal transduction (Science 2000, cited over 800 times).

In recent years, we have focused our effort on elucidating the signaling mechanism of a novel form of inflammatory cell death termed necroptosis.  In 2009, our group identified Receptor Interacting Protein kinase 3 (RIPK3) as a central mediator of necroptosis (Cell, 2009, cited over 1000 times).  Current projects include (1) deciphering the signaling mechanisms of necroptosis, (2) interrogation of the biology of RIPK3 and related necroptosis signaling molecules in intestinal wound healing and inflammation, (3) elucidation of the role of necroptosis in pathogen infections, and many others. 

We aim to take the knowledge we gain from basic pathway discovery to better understand the principles of immune regulation.  We believe our endeavor will pave the way for more efficacious therapeutic intervention in auto-inflammatory diseases, cancers and pathogen infections.

Current research projects in the lab include the following broad areas.  Interested students and postdoctoral candidates are encouraged to contact Dr. Chan for more information on rotation projects and research opportunities.

1. The role of necroptosis signal adaptors in inflammatory diseases
We are interested in how the kinases RIPK1 and RIPK3, both of which have critical functions in cell death, contribute to injury-induced inflammation and tissue repair.  Currently, we are using mouse models of intestinal injury and inflammation to study the function of these signal adaptors in intestinal homeostasis.

2. The role of cell death in anti-viral immune responses
We have discovered that necroptosis is an important innate immune defense mechanism against certain viruses.  We are interested in how host cell death during pathogen infections can alter the course of the host immune response.  On the other hand, we are also interested in exploring the mechanisms employed by different viral pathogens in combating the host cell death machinery.

3. Signaling mechanism of RIP kinases in cell death and inflammation
We found that the RIP kinases can promote inflammation through cell death-dependent and independent mechanisms.  What are the molecular events that regulate the diverse functions of the RIP kinases?  We are using biochemical, cell biological, and genetic tools to dissect the molecular regulation of these important immune signaling molecules.

Positions:

Professor of Immunology

Immunology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 1996

University of California - Berkeley

Grants:

Necroptosis signaling adaptors in inflammatory diseases

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

Viral mechanisms of necroptosis evasion

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

Viral inhibition of cell death in host immune responses

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

Publications:

Regulatory mechanisms of RIPK1 in cell death and inflammation.

Receptor Interacting Protein Kinase 1 (RIPK1) and RIPK3 are key adaptors that play critical roles in inflammatory and cell death signaling. Work in recent years have shown that their activities are tightly regulated by ubiquitination, phosphorylation and proteolysis. In addition to these post-translational modifications, the expression and activities of these kinases can further be tuned by environmental changes in pH and oxygen content. Proper control of these regulatory processes is crucial for the RIP kinases to execute their functions in immune responses and tissue homeostasis. In this review, we discuss recent advance in our understanding of the molecular mechanisms that regulate the activities of the RIP kinases. We will also discuss how the different regulatory mechanisms contribute to the functions of RIPK1 and RIPK3 in different pathophysiological settings.
Authors
Liu, Z; Chan, FK-M
MLA Citation
Liu, Zhijun, and Francis Ka-Ming Chan. “Regulatory mechanisms of RIPK1 in cell death and inflammation.Seminars in Cell & Developmental Biology, June 2020. Epmc, doi:10.1016/j.semcdb.2020.06.013.
URI
https://scholars.duke.edu/individual/pub1450875
PMID
32616439
Source
epmc
Published In
Seminars in Cell & Developmental Biology
Published Date
DOI
10.1016/j.semcdb.2020.06.013

The death-inducing activity of RIPK1 is regulated by the pH environment.

Receptor-interacting protein kinase 1 (RIPK1) is a serine/threonine kinase that dictates whether cells survive or die in response to the cytokine tumor necrosis factor (TNF) and other inflammatory stimuli. The activity of RIPK1 is tightly controlled by multiple posttranslational modification mechanisms, including ubiquitination and phosphorylation. Here, we report that sensitivity to TNF-induced, RIPK1-dependent cell death was tunable by the pH environment. We found that an acidic extracellular pH, which led to a concomitant decrease in intracellular pH, impaired the kinase activation of RIPK1 and autophosphorylation at Ser166 Consequently, formation of the cytosolic death-inducing complex II and subsequent RIPK1-dependent necroptosis and apoptosis were inhibited. By contrast, low pH did not affect the formation of membrane-anchored TNFR1-containing signaling complex (complex I), RIPK1 ubiquitination, and NF-κB activation. TNF-induced cell death in Ripk1-/- cells was not sensitive to pH changes. Furthermore, mutation of the conserved His151 abolished the pH dependence of RIPK1 activation, suggesting that this histidine residue functions as a proton acceptor to modulate RIPK1 activity in response to pH changes. These results revealed an unexpected environmental factor that controls the death-inducing activity of RIPK1.
Authors
Moriwaki, K; Balaji, S; Ka-Ming Chan, F
MLA Citation
Moriwaki, Kenta, et al. “The death-inducing activity of RIPK1 is regulated by the pH environment.Sci Signal, vol. 13, no. 631, May 2020. Pubmed, doi:10.1126/scisignal.aay7066.
URI
https://scholars.duke.edu/individual/pub1441486
PMID
32398349
Source
pubmed
Published In
Sci Signal
Volume
13
Published Date
DOI
10.1126/scisignal.aay7066

Leishmania braziliensis Subverts Necroptosis by Modulating RIPK3 Expression.

Leishmania braziliensis infection causes skin ulcers, typically found in localized cutaneous leishmaniasis (LCL). This tissue pathology associates with different modalities of cell necrosis, which are subverted by the parasite as a survival strategy. Herein we examined the participation of necroptosis, a specific form of programmed necrosis, in LCL lesions and found reduced RIPK3 and PGAM5 gene expression compared to normal skin. Assays using infected macrophages demonstrated that the parasite deactivates both RIPK3 and MLKL expression and that these molecules are important to control the intracellular L. braziliensis replication. Thus, LCL-related necroptosis may be targeted to control infection and disease immunopathology.
Authors
Luz, NF; Khouri, R; Van Weyenbergh, J; Zanette, DL; Fiuza, PP; Noronha, A; Barral, A; Boaventura, VS; Prates, DB; Chan, FK-M; Andrade, BB; Borges, VM
MLA Citation
Luz, Nivea F., et al. “Leishmania braziliensis Subverts Necroptosis by Modulating RIPK3 Expression.Front Microbiol, vol. 9, 2018, p. 2283. Pubmed, doi:10.3389/fmicb.2018.02283.
URI
https://scholars.duke.edu/individual/pub1355773
PMID
30323793
Source
pubmed
Published In
Frontiers in Microbiology
Volume
9
Published Date
Start Page
2283
DOI
10.3389/fmicb.2018.02283

The necroptosis adaptor RIPK3 promotes injury-induced cytokine expression and tissue repair.

Programmed necrosis or necroptosis is an inflammatory form of cell death that critically requires the receptor-interacting protein kinase 3 (RIPK3). Here we showed that RIPK3 controls a separate, necrosis-independent pathway of inflammation by regulating cytokine expression in dendritic cells (DCs). Ripk3(-/-) bone-marrow-derived dendritic cells (BMDCs) were highly defective in lipopolysaccharide (LPS)-induced expression of inflammatory cytokines. These effects were caused by impaired NF-κB subunit RelB and p50 activation and by impaired caspase 1-mediated processing of interleukin-1β (IL-1β). This DC-specific function of RIPK3 was critical for injury-induced inflammation and tissue repair in response to dextran sodium sulfate (DSS). Ripk3(-/-) mice exhibited an impaired axis of injury-induced IL-1β, IL-23, and IL-22 cytokine cascade, which was partially corrected by adoptive transfer of wild-type DCs, but not Ripk3(-/-) DCs. These results reveal an unexpected function of RIPK3 in NF-κB activation, DC biology, innate inflammatory-cytokine expression, and injury-induced tissue repair.
Authors
Moriwaki, K; Balaji, S; McQuade, T; Malhotra, N; Kang, J; Chan, FK-M
MLA Citation
Moriwaki, Kenta, et al. “The necroptosis adaptor RIPK3 promotes injury-induced cytokine expression and tissue repair.Immunity, vol. 41, no. 4, Oct. 2014, pp. 567–78. Pubmed, doi:10.1016/j.immuni.2014.09.016.
URI
https://scholars.duke.edu/individual/pub1342745
PMID
25367573
Source
pubmed
Published In
Immunity
Volume
41
Published Date
Start Page
567
End Page
578
DOI
10.1016/j.immuni.2014.09.016

A RNA interference screen identifies RIP3 as an essential inducer of TNF-induced programmed necrosis.

Authors
Cho, Y; Challa, S; Chan, FK-M
MLA Citation
Cho, Youngsik, et al. “A RNA interference screen identifies RIP3 as an essential inducer of TNF-induced programmed necrosis.Adv Exp Med Biol, vol. 691, 2011, pp. 589–93. Pubmed, doi:10.1007/978-1-4419-6612-4_62.
URI
https://scholars.duke.edu/individual/pub1342765
PMID
21153365
Source
pubmed
Published In
Advances in Experimental Medicine and Biology
Volume
691
Published Date
Start Page
589
End Page
593
DOI
10.1007/978-1-4419-6612-4_62