Project 03:

Nuclear quality control of non-imported mitochondrial precursor proteins

Fabian den Brave

E-Mail: denbrave@uni-bonn.de

Phone: +49 228-287-54150

Website

Institute of Biochemistry and Molecular Biology

University of Bonn

Axel Mogk

E-Mail: a.mogk@zmbh.uni-heidelberg.de

Phone: +49 6221-546863

Website

Zentrum für Molekulare Biologie (ZMBH)

Heidelberg University

Abstract

Impairment or overload of mitochondrial protein import lead to the cytosolic accumulation of mitochondrial precursor proteins (mitoPREs), which are prone to misfolding and aggregation. mitoPREs can be targeted to the nucleus for protein quality control (PQC), though the diverse nuclear proteostasis strategies and their physiological relevance remain poorly understood. We will define the role of the nucleus as important PQC hub for mitoPREs using Saccharomyces cerevisiae as model system. Here, we will put a special emphasis on nuclear J-domain proteins in handling mitoPREs.

Project-relevant publications

Mogk A, den Brave F (2024) Fine-tuning stress responses by auxiliary feedback loops that sense damage repair. J Cell Biol. 223(12): e202410205.

Ruger-Herreros C, Svoboda L, Mogk A, Bukau B (2024) Role of j-domain proteins in yeast physiology and protein quality control. J Mol Biol. 436(14):168484.

Schulte U, den Brave F, Haupt A, Gupta A, Song J, Muller CS, Engelke J, Mishra S, Mårtensson C, Ellenrieder L, Priesnitz C, Straub SP, Doan KN, Kulawiak B, Bildl W, Rampelt H, Wiedemann N, Pfanner N, Fakler B, Becker T (2023) Mitochondrial complexome reveals quality-control pathways of protein import. Nature. 614:153-159.

Borgert L, Mishra S, den Brave F (2022) Quality control of cytoplasmic proteins inside the nucleus. Comput Struct Biotechnol J. 20:4618-4625.

Jawed A, Ho CT, Grousl T, Shrivastava A, Ruppert T, Bukau B, Mogk A (2022) Balanced activities of Hsp70 and the ubiquitin proteasome system underlie cellular protein homeostasis. Front Mol Biosci. 9:1106477.

Li X, Straub J, Medeiros TC, Mehra C, den Brave F, Peker E, Atanassov I, Stillger K, Michaelis JB, Burbridge E, Adrain C, Münch C, Riemer J, Becker T, Pernas LF (2022) Mitochondria shed their outer membrane in response to infection-induced stress. Science. 375(6577):eabi4343.

Shrivastava A, Sandhof CA, Reinle K, Jawed A, Ruger-Herreros C, Schwarz D, Creamer D, Nussbaum-Krammer C, Mogk A, Bukau B (2022) The cytoprotective sequestration activity of small heat shock proteins is evolutionarily conserved. J Cell Biol. 221(10):e202202149.

den Brave F, Cairo LV, Jagadeesan C, Ruger-Herreros C, Mogk A, Bukau B, and Jentsch S (2020) Chaperone-mediated protein disaggregation triggers proteolytic clearance of intra-nuclear protein inclusions. Cell Rep. 31:107680.

Ho CT, Grousl T, Shatz O, Jawed A, Ruger-Herreros C, Semmelink M, Zahn R, Richter K, Bukau B, Mogk A (2019) Cellular sequestrases maintain basal Hsp70 capacity ensuring balanced proteostasis. Nat Commun. 10(1):4851.

Paasch F, den Brave F, Psakhye I, Pfander B, Jentsch S (2018) Failed mitochondrial import and impaired proteostasis trigger SUMOylation of mitochondrial proteins. J Biol Chem. 293:599-609.

All publications of the SPP2453