Crohn's disease is a severe inflammatory bowel disease that, although manageable with treatment, remains incurable due to a lack of understanding of its underlying molecular mechanisms. Various pieces of evidence suggest that cellular autophagy, an essential process for degrading and recycling unwanted cytoplasmic components, plays a protective role against this disease. However, genetic polymorphisms in members of the autophagic machinery (ATGs) increase the risk of developing it. Despite this, some ATGs also have noncanonical functions, distinct from canonical autophagy, raising questions about the relative contribution of canonical and non-canonical ATG mechanisms in protecting against this pathology. A detailed characterization of these protective mechanisms will facilitate the design of truly curative therapeutic approaches for this disease.

Previous studies conducted in Dr. Pimentel's laboratory indicate that the ATG16L1-T300A polymorphism (rs2241880), associated with a higher risk of Crohn's disease, does not alter canonical autophagy but interferes with non-canonical functions of ATG16L1. Specifically, it reduces its ability to induce non-canonical autophagy in response to the lysosomal transmembrane protein TMEM59 due to a defective interaction with the WD40 domain of ATG16L1. Preliminary data suggest that TMEM59 regulates lysosomal activity in intracellular defense against bacterial infections and that ATG16L1-T300A may increase the risk of this disease by impairing this defensive mechanism. This idea aligns with a general model proposing that the disease arises from defective control of the intestinal microbiota, which, in turn, triggers an uncontrolled inflammatory response.

his Doctoral Thesis Project will evaluate the hypothesis that TMEM59 is involved in lysosomal homeostasis and intracellular defense against bacterial infections through its ability to induce non-canonical autophagy mediated by the WD40 domain of ATG16L1 and will examine whether this mechanism is inhibited by the ATG16L1-T300A allele. To this end, a wide range of in vitro assays will be conducted using experimental systems lacking TMEM59, the WD40 domain of ATG16L1, or expressing the ATG16L1-T300A allele. Subsequently, genetically modified mice will be used to corroborate in vivo the functional interaction between these three elements. This project will provide mechanistic insights for a deeper understanding of the molecular basis of Crohn's disease.