Regulation of the NLRP3 Inflammasome by Posttranslational Modifications

Inflammasomes are multimeric cytosolic protein complexes that mediate the inflammatory response against microbial infections or cellular stress (1). The activation of the inflammasome triggers the activation of caspase-1, thereby allowing the maturation and secretion of the proinflammatory cytokines, IL-1β and IL-18 (1, 2). A typical inflammasome is composed of a sensor protein, such as a pattern recognition receptor, the adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD), and the effector caspase-1 (2). The first family of sensor proteins discovered to form inflammasomes was NOD-like receptors (NLRs), characterized by the presence of an N-terminal pyrin domain (PYD), a central nucleotide-binding domain (NACHT), and carboxy-terminal leucine-rich repeats (LRRs) motifs (2). In addition to NLR members (NLRP3, NLRP1, and NLRC4), the absent in melanoma 2 (AIM2)-like receptors (ALR) and retinoic acid inducible gene I (RIG-I)-like receptor (RLR) families also have been shown to play a role in the formation of inflammasomes (3). As a critical component of the innate immune system, they sense molecular structures present in pathogens (pathogen-associated molecular patterns) or endogenous molecules released from damaged cells (damage-associated molecular patterns), such as bacterial toxins, extracellular ATP, monosodium urate crystals, and RNA viruses to mediate an array of immune responses (4). To date, among inflammasome mem3bers, the NLRP3 inflammasome is the best characterized and widely studied because it responds to a wide array of physically and chemically diverse stimuli (5).

The activation of the NLRP3 inflammasome involves the integration of two signals that indicate cellular damage or stress. The first signal, also known as priming, is induced by bacterial toxins or pathogen-associated molecular patterns, such as LPS that acts on TLR4 and induces NF-κB–dependent transcription of NLRP3 and pro–IL-1β, as well as other inflammasome components (6, 7). However, in human monocytes, the priming step is sufficient to activate the inflammasome and IL-1β release (8, 9) via a nonclassical signaling pathway (10). Other NF-κB–activating stimuli, such as TNF, Pam3CSK, and IL-1, can also prime the cells before stimulation with inflammasome activators. However, NLRP3 is kept in an autosuppressed and inactive state, which is in part due to certain posttranslational modifications (PTMs), the topic of this review. Therefore, the NLRP3 inflammasome typically requires a second signal for assembly and activation, which consists of a multitude of pathogens and stress-associated danger signals. NLRP3-activating signals include host-derived molecules, such as extracellular ATP and hyaluronan released by dying or injured cells; amyloidogenic proteins, including β-amyloid, islet amyloid, and serum amyloid A; metabolic stress-like elevated extracellular glucose, palmitate, cholesterol crystals, and monosodium urate crystals; environmental irritants, such as silica, asbestos, and UVB irradiation; bacterial pore-forming toxins, such as Nigericin; skin irritants, such as trinitrophenylchloride, trinitrochlorobenzene, and dinitrofluorobenzene; and whole pathogens, such as certain bacteria, viruses, and fungi (6, 7, 11). Importantly, some of these signal 2 inducers can cause the activation of the NLRP3 inflammasome in human myeloid cells without the need for priming (12–16).

In response to signals 1 and 2, NLRP3 oligomerizes, thus forming a platform for the recruitment of ASC through homotypic PYD-PYD interaction. Key for NLRP3 oligomerization is NIMA-related kinase 7 (NEK7), a multifunctional serine-threonine kinase involved in DNA repair, mitochondrial regulation, and mitosis (17). NEK7 interacts with NLRP3 and together oligomerizes into a complex that is essential for ASC speck formation (18). ASC proteins then form filaments followed by oligomerization and recruitment of procaspase-1 via CARD-CARD interaction (19). This induces the autoproteolytic cleavage of procaspase-1 to yield active caspase-1 by proximity-mediated cleavage (6). Active caspase-1 then promotes the processing of pro–IL-1β and pro–IL-18 to their biologically active forms, IL-1β and IL-18 (6). In addition, active caspase-1 cleaves a pore-forming protein called gasdermin-D (GSDMD), which leads to the release of its N-terminal domain to form pores in the plasma membrane that facilitates the secretion of IL-1β and IL-18 into the extracellular matrix and induces a form of programmed cell death known as pyroptosis (20–22).

Although inflammasomes play an essential role in the host response against microbial products and invading pathogens, dysregulated inflammasome activation has been implicated in the pathogenesis of various autoinflammatory, autoimmune, and metabolic diseases. For instance, aberrant NLRP3 inflammasome activation caused by activating mutations in NLRP3 has been reported in diseases including cryopyrin-associated periodic syndrome (CAPS), Muckle–Wells syndrome, and neonatal-onset multisystem inflammatory disease (23). Also, overactivation of NLRP3 inflammasome contributes to diseases such as rheumatoid arthritis, gout, atherosclerosis, type 2 diabetes, and Alzheimer’s disease (23–25). Therefore, tight regulation of NLRP3 inflammasome activation is crucial to provide an adequate immune defense and to maintain immune homeostasis (24). Indeed, the underlying mechanism of NLRP3 inflammasome regulation has been extensively investigated, and various PTMs have been identified that regulate NLRP3 inflammasome activation. These modifications include ubiquitination, phosphorylation, SUMOylation, and S-nitrosylation (Fig. 1). In this review, we focus on the various PTMs involved in the regulation of NLRP3 inflammasome activation at the levels of NLRP3, ASC, and caspase-1.

As mentioned earlier, after priming, NLRP3 assumes an autoinhibited state, where the LRR domain folds back onto the NACHT domain, a confirmation stabilized in part by PTMs. Ubiquitination is the best-characterized form of PTMs that regulates the intensity of immune responses, such as NLRP3 inflammasome activation (26). Ubiquitination involves the addition of ubiquitin moieties to a lysine or N terminus of a target protein via isopeptide linkage, a process catalyzed by multiple enzymes, including E3 ubiquitin ligases (26). Several forms of ubiquitination have been shown to control NLRP3 inflammasome activation, including Lys63 (K63)-linked, Lys48 (K48)-linked, and linear (M1)-linked ubiquitination. Sequential steps of deubiquitination are required for optimal NLRP3 oligomerization and inflammation activation. Indeed, deubiquitinating enzymes that catalyze the removal of ubiquitin chains have been shown to be essential for the regulation of NLRP3 inflammasome. For example, the BRCAI/BRCA2-containing complex subunit 3 (BRCC3), a component of the BRCC36 isopeptidase complex (BRISC), acts as a positive regulator of NLRP3 activity by promoting deubiquitination of the LRR region of NLRP3, which normally occurs in unstimulated cells, thereby leading to its assembly and activation (27). A subsequent study by Ren et al. (28) provided mechanistic insights where they used knockout mice to demonstrate that Abraxas brother 1 recruits BRISC to NLRP3 to mediate BRISC-dependent deubiquitination of NLRP3 and subsequent interaction with ASC and inflammasome activation. Despite all the studies showing the role of K63-linked ubiquitination in controlling NLRP3 inflammasome activation, the specific E3 ubiquitin ligase(s) that catalyze NLRP3 ubiquitination has remained elusive. Recently, Tang et al. (29) showed that Ring Finger Protein 125 mediates K63-linked polyubiquitination of the LRR domain of NLRP3. This ubiquitination event then allows the recruitment of Casitas-B-lineage lymphoma protein-b to the LRR domain, which in turn targets NLRP3 for K48-linked polyubiquitination at Lys496 and subsequent proteasomal degradation, eventually leading to inhibition of NLRP3 inflammasome activation (29). Interestingly, several other E3 ubiquitin ligases were found to repress NLRP3 inflammasome activation by mediating its K48-linked polyubiquitination. These include F-box L2, MARCH7, tripartite motif 31, and Ariadne homolog 2 (30–33). F-box L2, a subunit of Skp-Cullin-F box, functions as an E3 ubiquitin ligase to mediate the polyubiquitination of NLRP3, leading to its proteasomal degradation and inhibition of NLRP3 inflammasome activation (30). Similarly, another E3 ubiquitin ligase, MARCH7, was shown to promote K48-linked polyubiquitination and autophagic degradation of the LRR and NACHT domains of NLRP3 downstream of the dopamine D1 receptor pathway (31). Additional E3 ligases, such as tripartite motif 31 and Ariadne homolog 2, have been demonstrated to inhibit NLRP3 inflammasome activation through similar processes of K48-linked polyubiquitination and subsequent proteasomal degradation of NLRP3 (32, 33).

Besides negative regulators, two E3 ligases that catalyze K63 ubiquitination, Pellino2 and TNFR-associated factor (TRAF) 6, were shown to positively regulate NLRP3 inflammasome activation during the priming phase of activation (34, 35). Pellino2, via its forkhead-associated (FHA) and really interesting new gene (RING)-like domains, enhances NLRP3-induced ASC oligomerization by mediating K63-linked polyubiquitination of NLRP3 (34). However, the mechanism by which this type of ubiquitination mediates NLRP3 inflammasome activation remains unclear (34). Another study found that TRAF6, via its E3 ligase activity, facilitates nontranscriptional priming of NLRP3 inflammasome and promotes ASC and NLRP3 oligomerization, yet the substrate of TRAF6-mediated K63 ubiquitination was not identified (35). Interestingly, a recent study demonstrated that the E2 ligase, Ubc13, which ubiquitinates and activates TRAF6 (36, 37), can directly interact with and mediate K63-linked polyubiquitination of NLRP3 at lysine residues Lys687 and Lys565, and thereby promotes NLRP3 inflammasome activation (38). However, the E3 ubiquitin ligase required for Ubc13-mediated polyubiquitination of NLRP3 remains unidentified, so it is interesting to speculate whether TRAF6 is the missing ligase.

The phosphorylation status of NLRP3 inflammasome components is critical during both priming and activation of the NLRP3 inflammasome. JNK1 phosphorylation of NLRP3 at Ser198 (S194 in mouse) during the priming step was shown to be a precursor for NLRP3 deubiquitination and self-association, which then drives NLRP3 inflammasome activation (28, 39). Blocking S194 phosphorylation by mutating serine to alanine or by inhibiting JNK1 in a mouse model of CAPS prevents NLRP3 inflammasome activation after priming, which makes JNK1 inhibition a potential target for CAPS or other NLRP3-related diseases (39). Interestingly, another study by Zhang et al. (40) demonstrated that phosphorylation of the NACHT domain of NLRP3 at residue S295 (S291 in mouse) by the Golgi-associated kinase protein kinase D releases NLRP3 from mitochondria-associated endoplasmic reticulum membranes to promote inflammasome assembly and activation. Importantly, pharmacological inhibition of protein kinase D blocked inflammasome activity in LPS-stimulated PBMCs from patients with autoactivatory mutations in NLRP3 (40). Contrastingly, Mortimer et al. (41) showed that protein kinase A (PKA) phosphorylates NLRP3 within the NACHT domain at Ser295 (S291 in mouse) and promotes both K48- and K63-linked ubiquitination and thereby inhibits NLRP3 inflammasome activation. Moreover, bile acids activate the TGR5-cAMP-PKA axis and induce PKA-dependent phosphorylation of NLRP3 at Ser295 (S291 in mouse), which leads to ubiquitination and subsequent inhibition of NLRP3 inflammasomes (42). Similarly, another study showed that phosphorylation of NLRP3 on its PYD domain at Ser5 (S3 in mouse) during the priming stage disrupts NLRP3 oligomerization and inflammasome activation (43). The same study showed that the phosphatase, PP2A, can reverse this process by dephosphorylating Ser5 (S3 in mouse) of NLRP3. A subsequent study demonstrated that AKT is the kinase that phosphorylates NLRP3 at Ser5 (S3 in mouse) and thereby disrupts the interaction between NLRP3 and ASC (44). Finally, Ephrin type-A receptor 2, a tyrosine kinase receptor selectively expressed in airway epithelial cells, negatively regulates inflammasome activation in a model of reovirus infection and OVA-induced asthma by phosphorylating NLRP3 at Tyr132, which interferes with its interaction with ASC and speck formation (45).

In addition to serine residues, phosphorylation and dephosphorylation of tyrosine residues of NLRP3 inflammasome components can regulate its activation. Indeed, dephosphorylation of NLRP3 at Tyr861 (Tyr859 in mouse) upon inflammasome induction by phosphatase protein tyrosine phosphatase nonreceptor 22 promotes activation of NLRP3 inflammasome (46). Although the kinase has not yet been identified, this study indicates that Tyr861 (Tyr859 in mouse) phosphorylation of NLRP3 can serve as an important brake on NLRP3 inflammasome activation, especially in the context of inflammatory bowel disease and colitis (46).

The cross-talk between the immune system and metabolism in the context of NLRP3 inflammasome regulation has been recently established. In addition to sensing metabolites (e.g., uric acid, palmitate, and cholesterol crystals), components of metabolic pathways, such as those generated during glycolysis, hexokinase, and mitochondrial ROS, have been shown to regulate the NLRP3 inflammasome, all of which have been thoroughly reviewed by Hughes et al. (47). Importantly, some of these metabolic components can cause PTMs of NLRP3 to modulate its activity, either directly or indirectly. For example, glutathione, an antioxidant that prevents cellular damage caused by overproduction of reactive oxygen species, has been shown to directly modify caspase-1, by S-glutathionylation, to limit its catalytic activity (48). Subsequently, Guglielmo et al. (49) reported that S-glutathionylation of NLRP3 itself may modulate its activation. The study demonstrated that deglutathionylation of NLRP3 by the anti-inflammatory compound, curcumin, favors its interaction with glutathionylated caspase-1, which possesses lower proteolytic activity and thereby limits inflammasome activation.

Other PTMs, including nitrosylation, SUMOylation, acetylation, and ADP-ribosylation, were found to be involved in the regulation of NLRP3 inflammasome activation. Previous studies demonstrated that NLRP3 SUMOylation can positively or negatively regulate the activation of NLRP3 inflammasome depending on the context. NLRP3 SUMOylation by the SUMO E3 ligase MAPL suppresses NLRP3 inflammasome activation, but after stimulation, the SUMO-specific proteases (SENP) 6 and SENP7 mediate NLRP3 deSUMOylation and subsequent activation (50). In contrast, another study showed that NLRP3 SUMOylation by SUMO1 at Lys204 promotes ASC oligomerization and NLRP3 inflammasome activation, a process regulated by SENP3 that deSUMOylates NLRP3 to decrease its activation (51). Moreover, acetylation of NLRP3 facilitates assembly and activation of the inflammasome, while its deacetylation by sirtuin-2 inhibits inflammasome activation and thereby contributes to protection against aging-associated chronic inflammation and insulin resistance (52). In addition, NO was shown to negatively regulate NLRP3 inflammasome activation via S-nitrosylation of NLRP3, although the specific residue of NLRP3 involved in S-nitrosylation remains to be identified (53–55). It is also unclear whether nitrosylation, like other PTMs, controls the priming signal or is induced as a negative feedback loop after inflammasome activation. Interestingly, certain pathogens have been shown to induce PTMs of NLRP3 to modulate its activity. For example, IFN-γ–induced NO after Mycobacterium tuberculosis infection leads to S-nitrosylation of NLRP3 and subsequent inflammasome inhibition. In contrast, ADP-ribosylation of NLRP3 by a Mycoplasma pneumoniae–derived ADP-ribosylating toxin, called community-acquired respiratory distress syndrome, promotes NLRP3 inflammasome activation, which may be linked to the exuberant inflammation associated with M. pneumoniae infections (52).

Filament formation and oligomerization of the adaptor protein, ASC, as well as its interaction with NLRP3 and caspase-1, can all be subject to posttranslational regulation. ASC can be targeted by K63-linked polyubiquitination and linear ubiquitination. In fact, K63-linked polyubiquitination of ASC was one of the earliest PTMs known to regulate inflammasome activation, where it was shown that after K63 ubiquitination, ASC associates with the autophagic adaptor, p62, and is then targeted for autophagic degradation, thereby leading to suppression of the NLRP3 inflammasome (56). Nevertheless, the E3-ubiquitin ligase that mediates this event has not been identified. In contrast, Guan et al. (57) showed that after vesicular stomatitis virus infection, mitochondrial antiviral signaling protein stabilizes ASC by recruiting TRAF3, an E3 ubiquitin ligase, which then directly catalyzes K63-linked polyubiquitination of ASC at Lys174 to promote ASC oligomerization and subsequent NLRP3 inflammasome activation. Intriguingly, ASC oligomerization can be regulated by the linear ubiquitin chain assembly complex (58). In this study, Rodgers et al. (58) showed that the heme-oxidized IRP2 ubiquitin ligase 1L subunit of linear ubiquitin chain assembly complex is required for ASC linear ubiquitination and the subsequent activation of NLRP3 inflammasome independently of NF-κB activation. Deubiquitinases, including ubiquitin-specific peptidase (USP) 7, USP47, and USP50, can regulate NLRP3 inflammasome activation by promoting ASC oligomerization and speck formation (59). Indeed, the inhibition of USP7 and USP47 resulted in reduced formation of ASC specks and IL-1β and IL-18 release (59). However, this study did not provide evidence on whether NLRP3 is the direct target of deubiquitination by USP7 and USP47, and data suggest that USP7/47 do not regulate the K48- or K63-linked ubiquitination of NLRP3. Similarly, USP50 can bind to ASC and catalyze the removal of K63-linked ubiquitin chains from ASC to induce inflammasome activation (60).

A study by Hara et al. (61) showed that spleen tyrosine kinase (SYK) and JNK were necessary for ASC phosphorylation at Tyr144 in mouse (Tyr146 in humans), which is critical for speck formation, subsequent caspase-1 activation, and ASC-dependent NLRP3 inflammasome activation. However, whether SYK and/or JNK directly phosphorylate ASC was not explored, and the exact mechanism of how this phosphorylation contributes to ASC oligomerization and subsequent inflammasome activation remains unknown (61). Chung et al. (62) later showed that SYK phosphorylates proline-rich tyrosine kinase 2, which then localizes to the ASC specks and directly phosphorylates ASC CARD domain at Tyr146. In addition, a recent study demonstrated that cAbl kinase is likely involved in ASC phosphorylation at Tyr146, and hence functions as a positive regulator of inflammasome activation (63). Intriguingly, IκB kinase α can act as a negative regulator of ASC by sequestering it in the perinuclear area via phosphorylation of Ser193 (Ser 195 in human), and the recruitment of the phosphatase PP2A following signal 2 of NLRP3 inflammasome activation facilitates the dissociation of IκB kinase α from ASC and thereby promotes NRLP3 inflammasome assembly and activation (64). Finally, using pharmacological inhibitors, Mambwe et al. (65) demonstrated that ASC phosphorylation at Tyr60 (Tyr135 in mouse) and Tyr137 (not conserved in mouse) can play additional roles in inflammasome activation.

The regulation of the inflammasome effector, caspase-1, plays an important role in controlling inflammasome activation. Phosphorylation of caspase-1 at Ser376 by the p21-activated kinase 1 has been shown to be important for caspase-1 activity and IL-1β secretion, although the mechanism was never elucidated (66). A study by Segovia et al. (67) suggested that neddylation, a PTM by a ubiquitin-like molecule called Nedd8, may promote the autocatalytic activity of procaspase-1 to yield active caspase-1 subunits (P20 and P10), and thereby lead to NLRP3 inflammasome activation. However, whether Nedd8-mediated activation of caspase-1 is directly due to neddylation of caspase-1 or indirectly via promoting other forms of ubiquitination of NLRP3 inflammasome components was not explored. In addition, K63-linked mediated polyubiquitination of the CARD domain of caspase-1 by a cellular inhibitor of apoptosis (cIAP1), cIAP2, and TRAF2-containing complex enhances caspase-1 activity, thereby inducing NLRP3 inflammasome activation (68). As mentioned earlier, superoxide dismutase 1 regulates caspase-1 activation by modulating the oxidation and S-glutathionylation of caspase-1–specific cysteine residues, Cys397 and Cys362 (48).

Furthermore, a few studies investigated PTMs of caspase-1 substrates, including GSDMD, IL-1β, and IL-18. GSDMD can be modified by metabolites, including fumarate and itaconate, that may alter its ability to form pores or be cleaved by caspase-1 (69, 70). Additional studies should uncover other PTMs of GSDMD, such as phosphorylation and ubiquitination, which are likely to occur as they do in other gasdermins (GSDMA and GSDME) (71). IL-1β itself can be potentially regulated at the posttranslational level, where initial evidence presented by Duong et al. (72) showed that polyubiquitination of pro–IL-1β on Lys163 in A20-deficient cells enhance its association with a complex containing caspase-1, caspase-8, and RIPK1, which in turn leads to increased cleavage and secretion of bioactive IL-1β. A recent study then demonstrated that postpriming, pro–IL-1β can be subject to K11-, K63-, and K48-linked ubiquitination, possibly by cIAP1, leading to its proteasomal degradation, as well as weakened processing by caspase-1, which reduces the availability of active IL-1β (73).

Over the past several years, studies identifying PTMs that regulate various components of the inflammasome have shed light on their significance in activating or restricting inflammasomes. Recent advances in the structural organization of the NLRP3 inflammasome and its components have been critical in our understanding of how NLRP3 inflammasomes oligomerize and assemble (reviewed in Refs. 74, 75). However, how phosphorylation and ubiquitination at various NLRP3 and ASC residues alter the conformation and structure of these proteins, and how that would affect the oligomerization and assembly of the inflammasome remain to be fully elucidated. For instance, it is likely that phosphorylation of the CARD domain is a critical step for cross-linking of ASC PYD domains and filament formation, a precursor for ASC oligomerization and speck formation. Alternatively, these PTMs may alter the recruitment of caspase-1 to ASC filaments. Likewise, modifications of NLRP3 NACHT and LRR domains are likely to alter the oligomerization of NLRP3 by influencing homotypic NACHT-NACHT or LRR-NEK7 interactions, respectively. PTMs of the NLRP3 PYD domain may affect the interaction with ASC PYD domain. However, additional studies are needed to fully investigate how these modifications alter the structure of NLRP3 and ASC and the subsequent oligomerization and caspase-1 recruitment. Understanding the underlying mechanisms of how these PTMs control inflammasomes is critical for the development of novel therapeutics for inflammasome-driven inflammatory diseases.

Only a paucity of research addresses the cross-talk between various PTMs and how that might influence NLRP3 inflammasome activation. For example, BRCC3-mediated deubiquitination of NLRP3 is enhanced after NLRP3 phosphorylation on Ser194 (39), indicating that phosphorylation of NLRP3 may be a precursor for deubiquitination and subsequent activation. In addition, phosphorylation of NLRP3 at Ser295 is likely an upstream regulator of ubiquitination and subsequent inhibition of NLRP3 activation (41, 42). Future studies are needed to investigate whether and how hierarchal control by multiple PTMs may positively or negatively affect NLRP3 inflammasome assembly and activation.

Interestingly, extracellular ASC specks, released after inflammasome activation, have been shown to play a role in the inflammatory response and autoinflammatory diseases, where they continue to serve as a platform for caspase-1 activation and IL-1β maturation (76, 77). Other inflammasome components also have been detected extracellularly (reviewed by Ref. 75). Thus, it is important to investigate whether PTMs of extracellular ASC, as well as other inflammasome components, may play a role in regulating caspase-1 activation and IL-1β maturation in the extracellular space.

Moreover, only a few studies explored how PTMs of caspase-1 may affect its catalytic activity, and none has examined whether other PTMs may alter the interaction of caspase-1 with the NLRP3 or other inflammasomes. Curiously, several PTMs, including ubiquitination, SUMOylation, nitrosylation, acetylation, and glutathionylation, have been shown to module the function and interaction of death caspases (reviewed by Ref. 78). Future studies should investigate whether additional PTMs occur in caspase-1 and how they affect its role in inflammasome activation. Finally, NEK7 is a core component of NLRP3 inflammasomes and is critical for its oligomerization. Importantly, NEK7 has been shown to be a substrate for phosphorylation and other PTMs (reviewed in Ref. 79). However, these PTMs have not yet been studied in the context of NLRP3 inflammasome activation.

The authors have no financial conflicts of interest.

Institutional History

• Assistant Professor, York University, Toronto, ON, Canada, 2016–current.

• Postdoctoral Fellow, University of Toronto, Toronto, ON, Canada, 2013–2016.

• Postdoctoral Scientist, Columbia University, New York City, NY, 2010–2013.

• Ph.D., University of California, Merced, Merced, CA, 2010.

• Research Assistant, American University of Beirut, Beirut, Lebanon, 2005–2006.

• M.Sc., American University of Beirut, Beirut, Lebanon, 2005.

• B.Sc., Haigazian University, Beirut, Lebanon, 2003.

Research Interests

• TRAF1 regulation of inflammation and inflammasomes, especially in the contexts of inflammatory arthritis.

• Role of individual type I IFN in viral infection and autoimmune diseases.

• Elucidating the molecular mechanisms through which exercise regulates the immune response.

Dr. Abdul-Sater was born in Beirut, Lebanon, where he grew up in the midst of a devastating civil war that led to the loss of countless lives and untold destruction. Abdul-Sater began his graduate studies at the American University of Beirut, where he investigated the transcriptional regulation of cyclooxygenases by statins and obtained his M.Sc. in 2005. Abdul-Sater’s research ethics, vision, and interests were influenced heavily by his thesis supervisor, Dr. Aida Habib. In 2006, Abdul-Sater left his home country for the very first time to pursue his academic career and fulfill his research interests and fascination in innate immune responses. In 2010, he completed his Ph.D. in immunology at the University of California, Merced, where he investigated host–pathogen interactions and inflammasome activation in response to Chlamydia trachomatis infections. He then moved to New York City, where he pursued his postdoctoral studies at Columbia University and studied interferon responses and bacterial cyclic dinucleotides in the Department of Microbiology and Immunology. At Columbia University he developed an interest in the regulation of inflammation. In 2013, Dr. Abdul-Sater moved to Canada and joined the Department of Immunology at the University of Toronto as a postdoctoral fellow in the laboratory of Dr. Tania Watts, where he investigated the role of TRAF1, a multifunctional adapter protein required for immune signaling, in lymphoma survival and in regulating inflammation. Dr. Abdul-Sater was then appointed as an Assistant Professor in 2016 and established his research group.

Ali A. Abdul-Sater, Ph.D.

Assistant Professor, York University, Toronto, ON, Canada