Yersinia-induced deregulation of cellular life and death signals in macrophages

• Applicants: Professor Dr. Klaus Ruckdeschel; Professor Dr. Andreas Tholey
• Subject Area: Medical Microbiology and Mycology, Hygiene, Molecular Infection Biology ; Parasitology and Biology of Tropical Infectious Disease Pathogens
• Term: from 2015 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 274839312

• Final Report Year: 2020

Final Report Abstract

By exploring the mechanisms of Yersinia enterocolitica-induced cell death induction a major part of the project contributed to disclose a so far unknown feedback signaling circuit that determines the fate of eukaryotic cells. A regulatory phosphorylation pathway from p38MAPK/MK2 to the kinase RIPK1 was identified as central signaling checkpoint at the crossroads of infection, inflammation and cell death. The molecular mechanisms and consequences thereof were deciphered in collaboration with colleagues of the Institute of Cell Biochemistry at the Medical School Hannover. This work implies the crosstalk between MK2 and RIPK1 as master control loop of cell vitality in multiple stress conditions, thus impacting a broad spectrum of physiological and pathophysiological biological processes, including infection, development, organ injury and cancer. This gave an example on how the investigation of the virulence traits of pathogenic bacteria may provide fundamental new insights into the regulation of host cell function and physiology.

Publications

• p38MAPK/MK2- dependent phosphorylation controls cytotoxic RIPK1 signalling in inflammation and infection. Nat Cell Biol. 2017; 19:1248-1259
  Menon MB, Gropengießer J, Fischer J, Novikova L, Deuretzbacher A, Lafera J, Schimmeck H, Czymmeck N, Ronkina N, Kotlyarov A, Aepfelbacher M, Gaestel M, Ruckdeschel K
  
• To die or not to die: Regulatory feedback phosphorylation circuits determine receptor-interacting protein kinase-1 (RIPK1) function. Mol Cell Oncol. 2017; 5(1):e1396389
  Menon MB, Gropengießer J, Ruckdeschel K, Gaestel M
  
• Serine 25 phosphorylation inhibits RIPK1 kinase-dependent cell death in models of infection and inflammation. Nat Commun. 2019; 10(1):1729
  Dondelinger Y, Delanghe T, Priem D, Wynosky-Dolfi MA, Sorobetea D, Rojas-Rivera D, Giansanti P, Roelandt R, Gropengiesser J, Ruckdeschel K, Savvides SN, Heck AJR, Vandenabeele P, Brodsky IE, Bertrand MJM