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

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

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:

Sweet modification and regulation of death receptor signaling pathway.

Death receptors, members of the tumor necrosis factor receptor (TNFR) superfamily, are characterized by the presence of a death domain in the cytosolic region. TNFR1, Fas, and TNF-related apoptosis-inducing ligand receptors, which are prototypical death receptors, exert pleiotropic functions in cell death, inflammation, and immune surveillance. Hence, they are involved in several human diseases. The activation of death receptors and downstream intracellular signaling are regulated by various post-translational modifications, such as phosphorylation, ubiquitination, and glycosylation. Glycosylation is one of the most abundant and versatile modifications to proteins and lipids, and it plays a critical role in the development and physiology of organisms, as well as the pathology of many human diseases. Glycans control a number of cellular events, such as receptor activation, signal transduction, endocytosis, cell recognition, and cell adhesion. It has been demonstrated that oligo- and monosaccharides modify death receptors and intracellular signaling proteins, and regulate their functions. Here, we review the current understanding of glycan modifications of death receptor signaling and their impact on signaling activity.
Authors
Moriwaki, K; Chan, FKM; Miyoshi, E
MLA Citation
Moriwaki, Kenta, et al. “Sweet modification and regulation of death receptor signaling pathway.J Biochem, Mar. 2021. Pubmed, doi:10.1093/jb/mvab034.
URI
https://scholars.duke.edu/individual/pub1477148
PMID
33752241
Source
pubmed
Published In
J Biochem
Published Date
DOI
10.1093/jb/mvab034

A class of viral inducer of degradation of the necroptosis adaptor RIPK3 regulates virus-induced inflammation.

The vaccine strain against smallpox, vaccinia virus (VACV), is highly immunogenic yet causes relatively benign disease. These attributes are believed to be caused by gene loss in VACV. Using a targeted small interfering RNA (siRNA) screen, we identified a viral inhibitor found in cowpox virus (CPXV) and other orthopoxviruses that bound to the host SKP1-Cullin1-F-box (SCF) machinery and the essential necroptosis kinase receptor interacting protein kinase 3 (RIPK3). This "viral inducer of RIPK3 degradation" (vIRD) triggered ubiquitination and proteasome-mediated degradation of RIPK3 and inhibited necroptosis. In contrast to orthopoxviruses, the distantly related leporipoxvirus myxoma virus (MYXV), which infects RIPK3-deficient hosts, lacks a functional vIRD. Introduction of vIRD into VACV, which encodes a truncated and defective vIRD, enhanced viral replication in mice. Deletion of vIRD reduced CPXV-induced inflammation, viral replication, and mortality, which were reversed in RIPK3- and MLKL-deficient mice. Hence, vIRD-RIPK3 drives pathogen-host evolution and regulates virus-induced inflammation and pathogenesis.
Authors
Liu, Z; Nailwal, H; Rector, J; Rahman, MM; Sam, R; McFadden, G; Chan, FK-M
MLA Citation
Liu, Zhijun, et al. “A class of viral inducer of degradation of the necroptosis adaptor RIPK3 regulates virus-induced inflammation.Immunity, vol. 54, no. 2, Feb. 2021, pp. 247-258.e7. Pubmed, doi:10.1016/j.immuni.2020.11.020.
URI
https://scholars.duke.edu/individual/pub1472584
PMID
33444549
Source
pubmed
Published In
Immunity
Volume
54
Published Date
Start Page
247
End Page
258.e7
DOI
10.1016/j.immuni.2020.11.020

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.Semin Cell Dev Biol, vol. 109, Jan. 2021, pp. 70–75. Pubmed, doi:10.1016/j.semcdb.2020.06.013.
URI
https://scholars.duke.edu/individual/pub1450875
PMID
32616439
Source
pubmed
Published In
Semin Cell Dev Biol
Volume
109
Published Date
Start Page
70
End Page
75
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

Frontline Science: Multiple cathepsins promote inflammasome-independent, particle-induced cell death during NLRP3-dependent IL-1β activation.

Sterile particles cause several chronic, inflammatory diseases, characterized by repeating cycles of particle phagocytosis and inflammatory cell death. Recent studies have proposed that these processes are driven by the NLRP3 inflammasome, a platform activated by phagocytosed particles, which controls both caspase-1-dependent cell death (pyroptosis) and mature IL-1β secretion. After phagocytosis, particles can disrupt lysosomes, and inhibitor studies have suggested that the resulting release of a lysosomal protease-cathepsin B-into the cytosol somehow activates NLRP3. However, using primary murine macrophages, we found that particle-induced cell death occurs independent of NLRP3/caspase-1 and depends instead on multiple, redundant cathepsins. In contrast, nigericin, a soluble activator of NLRP3 inflammasomes, induced cell death that was dependent on the NLRP3. Interestingly, nigericin-induced cell death depended partly on a single cathepsin, cathepsin X. By inhibiting or silencing multiple cathepsins in macrophages, several key proinflammatory events induced by sterile particles are blocked, including cell death, pro-IL-1β production, and IL-1β secretion. These data suggest that cathepsins might be potential therapeutic targets in particulate-mediated inflammatory disease. In support of this concept, we find that a broad-spectrum cathepsin inhibitor can suppress particle-induced IL-1-dependent peritonitis.
Authors
Orlowski, GM; Sharma, S; Colbert, JD; Bogyo, M; Robertson, SA; Kataoka, H; Chan, FK; Rock, KL
MLA Citation
Orlowski, Gregory M., et al. “Frontline Science: Multiple cathepsins promote inflammasome-independent, particle-induced cell death during NLRP3-dependent IL-1β activation.J Leukoc Biol, vol. 102, no. 1, July 2017, pp. 7–17. Pubmed, doi:10.1189/jlb.3HI0316-152R.
URI
https://scholars.duke.edu/individual/pub1342717
PMID
28087651
Source
pubmed
Published In
J Leukoc Biol
Volume
102
Published Date
Start Page
7
End Page
17
DOI
10.1189/jlb.3HI0316-152R