2. Academic Validation
  3. Proteolytic Activity of the Paracaspase MALT1 Is Involved in Epithelial Restitution and Mucosal Healing

Proteolytic Activity of the Paracaspase MALT1 Is Involved in Epithelial Restitution and Mucosal Healing

  • Int J Mol Sci. 2023 Apr 17;24(8):7402. doi: 10.3390/ijms24087402.
Leonie Wittner 1,  Lukas Wagener 1,  Jakob J Wiese 2,  Iris Stolzer 1,  Susanne M Krug 3,  Elisabeth Naschberger 4,  Rene Jackstadt 5,  Rudi Beyaert 6,  Raja Atreya 1 7 8 9,  Anja A Kühl 8 9 10,  Gregor Sturm 11,  Miguel Gonzalez-Acera 1,  Jay V Patankar 1 8 9,  Christoph Becker 1 7 8 9,  Britta Siegmund 2 8 9,  Zlatko Trajanoski 8 9 11,  Beate Winner 7 12 13,  Markus F Neurath 1 6 8 9,  Michael Schumann 2 8 9,  Claudia Günther 1 7 8 9
Affiliations

Affiliations

  • 1 Department of Medicine 1, Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany.
  • 2 Department of Gastroenterology, Rheumatology and Infectious Diseases, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, 12203 Berlin, Germany.
  • 3 Clinical Physiology/Nutritional Medicine, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, 12203 Berlin, Germany.
  • 4 Division Molecular and Experimental Surgery, Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany.
  • 5 Cancer Progression and Metastasis Group, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
  • 6 VIB-UGent Center for Inflammation Research, Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium.
  • 7 Deutsches Zentrum Immuntherapie, Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany.
  • 8 IBDome Consortium, 91054 Erlangen, Germany.
  • 9 IBDome Consortium, 12203 Berlin, Germany.
  • 10 iPATH.Berlin-Core Unit, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, 12203 Berlin, Germany.
  • 11 Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria.
  • 12 Department of Stem Cell Biology, Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany.
  • 13 Center of Rare Diseases (ZSEER), University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany.
PMID: 37108564 DOI: 10.3390/ijms24087402
Abstract

The paracaspase MALT1 is a crucial regulator of immune responses in various cellular contexts. Recently, there is increasing evidence suggesting that MALT1 might represent a novel key player in mucosal inflammation. However, the molecular mechanisms underlying this process and the targeted cell population remain unclear. In this study, we investigate the role of MALT1 proteolytic activity in the context of mucosal inflammation. We demonstrate a significant enrichment of MALT1 gene and protein expression in colonic epithelial cells of UC patients, as well as in the context of experimental colitis. Mechanistically we demonstrate that MALT1 protease function inhibits Ferroptosis, a form of iron-dependent cell death, upstream of NF-κB signaling, which can promote inflammation and tissue damage in IBD. We further show that MALT1 activity contributes to STAT3 signaling, which is essential for the regeneration of the intestinal epithelium after injury. In summary, our data strongly suggests that the protease function of MALT1 plays a critical role in the regulation of immune and inflammatory responses, as well as mucosal healing. Understanding the mechanisms by which MALT1 protease function regulates these processes may offer novel therapeutic targets for the treatment of IBD and other inflammatory diseases.

Keywords

ferroptosis; mucosal wound healing; ulcerative colitis.

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