With the rapidly increasing prevalence of autoimmune and inflammatory diseases, understanding the complexity of the underlying signaling mechanisms has become one of the most urgent scientific challenges. We harness the explosion of omics data and the growing catalogue of genetic defects to uncover how signaling shapes the human immune system and disease development. Collaboration with clinical immunologists and geneticists enables us to translate insights from genetic defects into a deeper understanding of immune regulation in humans. More specifically, we aim to identify new molecules and mechanisms involved in skin and gut inflammation, immunodeficiency disease, and cancer. For this, mechanistic studies in cellular models are combined with in-depth phenotyping of patients and gene-targeted mouse models. To maximize translational impact, mechanistic research is closely integrated with application-driven tech transfer activities.

Major research lines:

(1) MALT1 paracaspase-mediated CBM signaling in immune and non-immune cells.

Our original discovery that MALT1 holds a unique proteolytic activity in lymphocytes has led to a conceptual breakthrough in the understanding of CBM (CARD11-BCL10-MALT1) complex signaling dynamics and immune regulation (Coornaert et al, Nature Immunol, 2008). Within this complex, MALT1 functions as both a scaffold and a unique protease with a pivotal role in TCR- and BCR-induced NF-κB activation. MALT1 also forms cell-type specific CBM complexes with CARD11-related proteins (CARD9, CARD10, CARD14), extending its influence to diverse immune and non-immune cells. This broad biological scope opens new avenues for understanding MALT1’s role in health and disease and for therapeutic targeting of MALT1 signaling in inflammatory disease and cancer (Demeyer et al, iScience, 2020). Structure–function analysis in cellular models and detailed phenotypc analysis in newly generated mouse models allows us to study the role of different MALT1 substrates and the effect of genetic variants of CARDx proteins in tissue homeostasis and disease development (Skordos et al FEBS J, 2023; Staal et al FEBS J, 2021 and 2024; Iliaki et al., Biochem Pharmacol, 2024; Skordos et al, EMBO Rep, 2026). In this context, we also showed an important effect of the expression of genetic variants of CARD14 in epithelial cells in the development of skin and intestinal inflammatory diseases (Van Nuffel et al, EMBO Rep, 2020; Aidarova et al, EMBO Mol Med) and cancer (Vanneste et al, Biomedicines, 2022).

(2) Inborn errors of immunity as 'experiments of nature'

The unbiased discovery of causal genetic lesions via forward genetics in patients who have a rare disease elucidates a particularly impactful set of genotype-phenotype relationships. Inborn errors of immunity (IEI), also known as primary immune deficiencies (PID), are a heterogenous group of rare, life-threatening genetic disorders of the immune system that have been associated with ~500 disease-causing genes. Improved functional analysis of genetic defects and immune responses in PID patients allows for the validation of genotype-phenotype effects and provides novel insights in immunity. In the frame of the VIB Grand Challenges project on PID, a multidisciplinary translational initiative that addresses the urgent need for molecular diagnostic tools to better identify and classify PID patients and guide therapeutic decisions in the clinic, we developed cell- and murine models for genetic variants of novel and previously known PID genes, and successfully demonstrated their pathogenicity through functional validation (Tavernier et al, Nature Comm, 2019; Naesens et al, J Clin Immunol 2022; Naesens et al, Science Immunol, 2022). Novel insights from the PID team could also be swiftly translated into new diagnostic and therapeutic solutions for patients that have been often overlooked in the past. The inter- and transdisciplinarity of the PID project lead to structural, long-term collaborations with clinicians and academic partners, exemplified by the PID 2.0 VIB Grand Challenges validation project that started in 2024. This project sets out to scientifically, technically and clinically validate the interferon score test, its diagnostic/theragnostic utility in different international patient cohorts and develop it into a clinical-grade diagnostic test. Both PID projects are coordinated by Prof. Rudi Beyaert (https://vib.be/en/research-and-impact/grand-challenges-program/selected-projects/pid; https://vib.be/en/research-and-impact/grand-challenges-program/selected-projects/pid-20/pid-20-project).

(3) Ubiquitin signaling in inflammation and immunity.

Ubiquitin is a small protein that plays a crucial role in regulating protein turnover and cellular signaling pathways. Ubiquitin can form different types of chains on target proteins, and these chains can signal different outcomes. We investigate how dysregulation of ubiquitin pathways contribute to inflammation (Holgado et al., JACI, 2023; Skordos et al., EMBO Rep, 2026). For this, we have also developed multiple conditional gene-targeted mouse models.