This week on TIBDI: Impressive results in Nature show how gene mutations cause reduced autophagy, and mutations in the XIAP gene lead to early-onset CD in male patients.
From an Autophagy Gene to Crohn’s Disease
Genome wide association scans confirmed the importance of ATG16L1 mutations in Crohn’s disease (CD), especially a variant consisting of an Alanine to Threonine exchange at the 300th amino acid. Despite an abundance of literature, the precise mechanism linking the mutation to reduced autophagy was unknown. Dr. Aditya Murthy from Genentech, Inc. has now found an answer. The mutation is located in a cleavage site for the enzyme caspase-3, and it makes the protein more susceptible to cleavage. Caspase-3 is well known for its role in initiating apoptosis during cellular trauma, for instance during metabolic stress or intestinal infection. Without proper autophagy, macrophages are unable to neither regulate their energy consumption nor properly eliminate pathogens, and have an heightened inflammatory response.
XIAP Mutations in Early Onset CD
Variants in the gene encoding for the X-linked inhibitor of apoptosis protein (XIAP) can sometimes lead to intestinal inflammation. XIAP is involved with a multitude of processes including NOD signaling, apoptosis and NKT cell development. To investigate XIAP’s possible role in CD, Dr. Yvonne Zeissig and her colleagues at the University Medical Center Schleswig-Holstein in Germany, looked at CD patient samples to find if there were clear associations between XIAP and immune cell function. She found that approximately 4% of male early-onset CD patients had unique mutations in their XIAP genes. Experiments with patient primary cells revealed that loss of XIAP function caused defects in NOD1/2 signaling.
- Murthy, A., Li, Y., Peng, I., Reichelt, M., Katakam, A. K., Noubade, R., et al. (2015). A Crohn’s disease variant in Atg16l1 enhances its degradation by caspase 3. Nature, 506(7489), 456–462. doi:10.1038/nature13044
- Zeissig, Y., Petersen, B. S., Milutinovic, S., Bosse, E., Mayr, G., Peuker, K., et al. (2014). XIAP variants in male Crohn’s disease. Gut. doi:10.1136/gutjnl-2013-306520