prof. Mathieu Bertrand (PhD)

My group has made seminal contributions to our understanding of how cell survival, cell death, and inflammatory responses are regulated downstream of members of the TNF receptor superfamily and pattern recognition receptors. Our work contributed to reshaping the field by demonstrating that dysregulated cell death is not merely a consequence of inflammation but can act as a primary trigger for inflammatory pathologies. This insight has opened entirely new therapeutic perspectives, exemplified by the recent clinical development and use of RIPK1 kinase inhibitors. A hallmark of our research is the dissection of the molecular checkpoints that protect cells from TNF-induced cytotoxicity and the elucidation of the pathological outcomes when these checkpoints are chronically inactivated. W have uncovered how these molecular safeguards are intricately connected to host immune strategies for pathogen control, revealing that transient, regulated cell death can function as a “fail-safe” mechanism to ensure effective immune responses when pathogens attempt to subvert inflammatory signalling. One of my landmark discoveries was identifying that the protective role of cIAP1/2 in the TNF pathway stems from their ability to conjugate RIPK1 with non-degradative ubiquitin chains—an upstream and essential event in the activation of NF-κB and MAPK signalling. Building on this, my group demonstrated that kinases from these same pathways, namely IKKα/β and MK2, directly phosphorylate and inhibit RIPK1, thereby repressing TNF-mediated cell death. These findings revealed an elegant feedback control system in which survival signalling actively restrains the cell death machinery. More recently, we discovered an unconventional, LC3-independent form of selective macroautophagy that protects cells from TNF cytotoxicity by promoting lysosomal degradation of the cytosolic caspase-8-activating complex that forms upon TNF sensing. This unexpected connection between autophagy and death receptor signalling highlights the multi-layered nature of cellular defence mechanisms and provides yet another avenue for therapeutic exploitation. Through a combination of conceptual advances, mechanistic dissection, and translational relevance, our work has defined new paradigms in the control of inflammation and cell death. The discoveries from the lab have not only advanced fundamental biology but have also laid the groundwork for novel therapeutic strategies in inflammatory and infectious diseases, as well as in cancer.
 

• Prof. Mathieu Bertrand – principal investigator, full professor
• dr. Jon Huyghe (PhD) – post-doctoral fellow
• dr. Dario Priem (PhD) – post-doctoral fellow
• dr. Tom Delanghe (PhD) – post-doctoral fellow
• Annelore Haems – doctoral fellow
• Emma Van Valckenborgh – doctoral fellow
   

• LC3-independent autophagy prevents a TNF-driven type I interferonopathy. Immunity. 2025. Accepted. (IF 2024: 26.3)
• TAB2 controls a TAK1-independent cell death checkpoint at the level of TNFR1 Complex II in the TNF pathway. Cell Death Diff. 2025. Accepted. (IF 2024: 15.4)
• Death by TNF: a road to inflammation. Nat Rev Immunol. 2023. May;23(5):289-303. (IF 2023: 67.7) (710 citations)
• ATG9A prevents TNF cytotoxicity by an unconventional lysosomal targeting pathway Science. 2022. Dec 16;378(6625):1201-1207. (IF 2023: 56.9) (32 citations)
• Two distinct ubiquitin-binding motifs in A20 mediates its anti-inflammatory and cell protective activities. Nat Immunol. 2020. Apr;21(4):381-387. (IF 2023: 25.6) (66 citations)
• Serine 25 phosphorylation inhibits RIPK1 kinase-dependent cell death in models of infection and inflammation. Nat Commun. 2019. Apr 15;10(1):1729. (IF 2019: 12.1) (178 citations)
• MK2 phosphorylation of RIPK1 regulates TNF-mediated cell death Nat Cell Biol. 2017. Oct;19(10):1237-1247 (IF 2017: 19.0) (215 citations)
• NF-kB-independent role of IKKa/IKKb in preventing RIPK1 kinase-dependent apoptotic and necroptotic cell death during TNF signaling. Mol Cell. 2015. Oct 1;60(1):63-76. (IF 2015: 14.0) (481 citations)
• Cellular inhibitors of apoptosis cIAP1 and cIAP2 are required for innate immunity signaling by the pattern recognition receptors NOD1 and NOD2. Immunity. 2009. Jun 19;30(6):789-801. (IF 2009: 32.4) (420 citations)
• cIAP1 and cIAP2 facilitate cancer cell survival by functioning as E3 ligases that promote RIP1 ubiquitination. Mol Cell. 2008. Jun 20;30(6):689-700. (IF 2008: 10.3) (1363 citations)
   

• Lab address: VIB-UGent Center for Inflammation Research; Fiers-Schell-Van Montagu building; Technologiepark-Zwijnaarde 71; B-9052 Ghent; Belgium
• Bertrand team
• Prof. Bertrand is interested to receive invitations for presentations or talks