Work group of Prof. Krüger

Protein homeostasis control by the ubiquitin-proteasome system

Our research group primarily focuses on the mechanisms by which the ubiquitin-proteasome system (UPS) governs protein homeostasis (also referred to as “proteostasis”) under physiological and/or pathological conditions. Our main objective is to understand the processes of homeostasis perturbations at the crossroad between oxidative stress and the immune response. The UPS serves as the principal non-lysosomal mode of protein breakdown, thereby fining-tune the balance between protein synthesis, quality control and degradation and controlling the availability of a vast number of signal molecules regulating many cellular processes. Because such balance may be disturbed through oxidative stress, the UPS may be defined as a major component of the cellular anti-oxidative defense. Oxidative stress targets both cytosolic and secretory proteins, the latter being eliminated by the endoplasmic reticulum-associated degradation (ERAD) pathway. By the supply of MHC class I-restricted antigenic peptides from self and/or viral proteins recognized by CD8+ by cytotoxic T cells (CTL) the UPS is actively involved in the adaptive immune response. The UPS also plays a critical role during innate immunity by protecting cells and tissues against harmful reactions through the systematic elimination of damaged and/or oxidized proteins. Overall, our group pursues basic and translational research on topics related to medical biochemistry, biochemistry and pathobiochemistry with the aim of uncovering the pathogenesis of diseases associated with perturbed protein homeostasis such as auto-inflammatory diseases, cancer, infectious diseases and neurodegenerative diseases. Our work is supported by the German Research Foundation and the Fritz Thyssen Foundation.

References

  • Seifert et al. Immunoproteasomes preserve protein homeostasis upon interferon-induced oxidative stress. Cell 142, 613-624. (2010)
  • Steffen et al. Proteasomal degradation is transcriptionally controlled by TCF11 via an ERAD dependent feedback loop. Mol Cell 40(1):147-58. (2010)
  • Kriegenburg, et al. Redox control of proteasomal function: From molecular mechanisms to functional significance. Antioxid Redox Signal. 15(8):2265-99. (2011)
  • Krüger and Kloetzel. Immunoproteasomes at the interface of innate and adaptive immune responses: two faces of one enzyme. Curr Opin Immunol. 24 (1): 77-83 (2012)
  • Brehm et al. Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production, J Clin Invest. 125(11): 4196-211 (2015)
  • Brehm and Krüger. Dysfunction in protein clearance by the proteasome: impact on autoinflammatory diseases, Seminars in Immunopathology 37(4):323-33. (2015)
  • Sotzny et al. TCF11/Nrf1-mediated induction of proteasome expression prevents cytotoxicity by Rotenone. Antioxid Redox Signal. 25(16):870-885 (2016)
  • Ebstein und Krüger. Regulation der Proteostase – ein Fokus auf das Ubiquitin-Proteasomen-System. Biospektrum 04/17:379-383