Functional role of PGAM5 in epithelial homeostasis and colorectal cancer

• Applicant: Professor Dr. Christoph Becker
• Subject Area: Gastroenterology
• Term: from 2018 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 414209099

• Final Report Year: 2024

Final Report Abstract

The mitochondrial phosphatase PGAM5 exerts critical regulatory functions in cell death regulation and mitochondrial homeostasis. We hypothesized that PGAM5 might be a key regulator of gut tissue homeostasis and colorectal cancer development. To evaluate this hypothesis was the aim of this proposal. PGAM5 knock out mice did not exhibit overt alterations in gut architecture, intestinal epithelial cell composition, cell death rates, or overall survival indicating, to our surprise, that under steady state conditions, PGAM5 is dispensable for gut tissue homeostasis. We also explored the impact of PGAM5 in the lung and challenged PGAM5 deficient mice in a bleomycin-induced model of fibrosis. Although we could not identify a lung phenotype in the steady state, Pgam5-/- mice displayed significantly reduced lung fibrosis when compared to controls. PGAM5 impaired mitochondrial integrity in the lung epithelium on a functional and structural level independently of mtROS-production. Conversely, reduced mitophagy caused by PGAM5 deficiency improved mitochondrial homeostasis. These findings on PGAM5 led us to investigate PGAM5 also under other conditions of cellular stress. As our studies identified a role for PGAM5 in regulating interferon responses, we studied the function of PGAM5 in response to cytoplasmic nucleic acids. In a study by Yu et al. 2020, we could show that dsRNA induces PGAM5 oligomerization and direct interaction with the mitochondrial antiviral-signaling protein MAVS. PGAM5-deficient cells exhibited decreased expression of IFNβ and its target genes, along with reduced phosphorylation levels of IRF3 and TBK1 in response to intracellular dsRNA. Additionally, PGAM5-deficient cells exposed to vesicular stomatitis virus displayed compromised IFNβ expression and increased VSV replication, underscoring PGAM5's role in antiviral responses. In a collaboration with the group of Florian Greten (Frankfurt), PGAM5 was found to play a central role in the Urolithin A induction of T memory stem cells with effective anti-tumor T cell responses. Given the role of PGAM5 in regulating mitochondrial dynamics, we also studied the role of mitochondrial fission and fusion and could identify a key role for epithelial mitochondrial fusion in gut homeostasis. These findings are currently studied in a follow-up DFG-grant. A manuscript is currently under review.

Publications

• PGAM5 is a key driver of mitochondrial dysfunction in experimental lung fibrosis. Cellular and Molecular Life Sciences, 76(23), 4783-4794.
  Ganzleben, Ingo; He, Gui-Wei; Günther, Claudia; Prigge, Elena-Sophie; Richter, Karsten; Rieker, Ralf J.; Mougiakakos, Dimitrios; Neurath, Markus F. & Becker, Christoph
  
• PGAM5-MAVS interaction regulates TBK1/ IRF3 dependent antiviral responses. Scientific Reports, 10(1).
  Yu, Yu-qiang; Zielinska, Marta; Li, Wei; Bernkopf, Dominic B.; Heilingloh, Christiane Silke; Neurath, Markus F. & Becker, Christoph
  
• Autophagy in Cancer Therapy—Molecular Mechanisms and Current Clinical Advances. Cancers, 13(21), 5575.
  Ganzleben, Ingo; Neurath, Markus F. & Becker, Christoph
  
• Epithelial presenilin-1 drives colorectal tumour growth by controlling EGFR-COX2 signalling. Gut, 72(6), 1155-1166.
  Gamez-Belmonte, Reyes; Mahapatro, Mousumi; Erkert, Lena; Gonzalez-Acera, Miguel; Naschberger, Elisabeth; Yu, Yuqiang; Tena-Garitaonaindia, Mireia; Patankar, Jay V.; Wagner, Yara; Podstawa, Eva; Schödel, Lena; Bubeck, Marvin; Neurath, Markus F.; Stürzl, Michael & Becker, Christoph
  
• Expansion of T memory stem cells with superior anti-tumor immunity by Urolithin A-induced mitophagy. Immunity, 55(11), 2059-2073.e8.
  Denk, Dominic; Petrocelli, Valentina; Conche, Claire; Drachsler, Moritz; Ziegler, Paul K.; Braun, Angela; Kress, Alena; Nicolas, Adele M.; Mohs, Kathleen; Becker, Christoph; Neurath, Markus F.; Farin, Henner F.; Buchholz, Christian J.; Andreux, Pénélope A.; Rinsch, Chris & Greten, Florian R.
  
• SMYD2 targets RIPK1 and restricts TNF-induced apoptosis and necroptosis to support colon tumor growth. Cell Death & Disease, 13(1).
  Yu, Yu-qiang; Thonn, Veronika; Patankar, Jay V.; Thoma, Oana-Maria; Waldner, Maximilian; Zielinska, Marta; Bao, Li-li; Gonzalez-Acera, Miguel; Wallmüller, Stefan; Engel, Felix B.; Stürzl, Michael; Neurath, Markus F.; Liebing, Eva & Becker, Christoph
  
• The Role of Programmed Necrosis in Colorectal Cancer. Cancers, 14(17), 4295.
  Yu, Yu-Qiang; Gamez-Belmonte, Reyes; Patankar, Jay V.; Liebing, Eva & Becker, Christoph
  
• Functional and spatial proteomics profiling reveals intra- and intercellular signaling crosstalk in colorectal cancer. iScience, 26(12), 108399.
  Plattner, Christina; Lamberti, Giorgia; Blattmann, Peter; Kirchmair, Alexander; Rieder, Dietmar; Loncova, Zuzana; Sturm, Gregor; Scheidl, Stefan; Ijsselsteijn, Marieke; Fotakis, Georgios; Noureen, Asma; Lisandrelli, Rebecca; Böck, Nina; Nemati, Niloofar; Krogsdam, Anne; Daum, Sophia; Finotello, Francesca; Somarakis, Antonios; Schäfer, Alexander ... & Trajanoski, Zlatko