Molecular Biology I
Molecular Biology I
Faculty of Biology
Center of Medical Biotechnology (ZMB)
University of Duisburg-Essen
Cellular homeostasis, proliferation and stress responses
Cells need to cope with a multitude of stress conditions that relentlessly inflict damage to its most vital components. This includes insults to the DNA that threatens genome stability, damage of proteins that can then form toxic aggregates, or injury of whole organelles such as mitochondria and lysosomes that releases harmful components. Cells have developed sophisticated molecular responses to these stresses that maintain protein homeostasis and organelle function, and ensure genomic stability.
We are interested in deciphering these responses and uncover how they counteract stress-induced cell death and aging-related degeneration, or maintain cell proliferation.
The ubiquitin-proteasome system (UPS) is critically involved in cellular stress responses. Ubiquitination triggers degradation of damaged proteins by the proteasome, or removal of protein aggregates or hole organelles in the lysosome through autophagy. In addition, it regulates signalling pathways such as the DNA damage response and coordinates them with cell cycle progression.
A focus of our research has been the AAA+-type ATPase VCP/p97, which has emerged as a pivotal element of the UPS. It governs a variety of processes such as ER-associated degradation, ribosomal quality control, DNA damage responses as well as autophagy.
Mutations in VCP/p97 in humans cause degenerative diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), while pharmacological inhibition of VCP/p97 is considered as a strategy in cancer therapy. We have been working to reveal the molecular function of VCP/p97 and to understand how it cooperates with a host of accessory factors to trigger diverse stress responses in different compartments.
Distribution of published plasmids through addgene.org.
Keywords: Cellular stress responses, proteostasis, ubiquitin-proteasome system, autophagy, lysosomal membrane permeabilization, lysophagy, mitophagy, DNA damage response, double strand break repair, cell cycle regulation.
Kracht M, van den Boom J, Seiler J, Kröning A, Kaschani F, Kaiser M, Meyer H. Protein phosphatase-1 complex disassembly by p97 is initiated through multivalent recognition of catalytic and regulatory subunits by the p97 SEP- domain adapters. J Mol Biol. 2020 Oct 12:S0022-2836(20)30576-3.
Koerver L, Papadopoulos C, Liu B, Kravic B, Rota G, Brecht L, Veenendaal T, Polajnar M, Bluemke A, Ehrmann M, Klumperman J, Jäättelä M, Behrends C, Meyer H. The ubiquitin-conjugating enzyme UBE2QL1 coordinates lysophagy in response to endolysosomal damage. EMBO Rep., 2019, doi: 10.15252/embr.201948014.
Weith M, Seiler J, van den Boom J, Kracht M, Hülsmann J, Primorac I, del Pino Garcia J, Kaschani F, Kaiser M, Musacchio A, Bollen M, Meyer H. Ubiquitin-independent disassembly by a p97 AAA-ATPase complex drives PP1 holoenzyme formation. Mol Cell, 2018, doi: 10.1016/j.molcel.2018.09.020.
Papadopoulos C, Meyer H. Detection and Clearance of Damaged Lysosomes by the Endo-Lysosomal Damage Response and Lysophagy. Curr Biol. 2017 Dec 18;27(24):R1330-R1341.
van den Boom J, and Meyer H. VCP/p97-Mediated Unfolding as a Principle in Protein Homeostasis and Signaling. Mol. Cell, 2017, doi: 10.1016/j.molcel.2017.10.028. Review.
Papadopoulos C, Kirchner P, Bug M, Grum D, Koerver L, Schulze N, Poehler R, Dressler A, Fengler S, Arhzaouy K, Lux V, Ehrmann M, Weihl CC, Meyer H. VCP/p97 cooperates with YOD1, UBXD1 and PLAA to drive clearance of ruptured lysosomes by autophagy. EMBO J 2017 Jan 17;36(2):135-150.
van den Boom J, Wolf M, Weimann L, Schulze N, Li F, Kaschani F, Riemer A, Zierhut C, Kaiser M, Iliakis G, Funabiki H, Meyer H. VCP/p97 extracts sterically trapped Ku70/80 rings from DNA in double strand break repair. Mol. Cell, 2016, 64: 189–198.
Eiteneuer A, Seiler J, Weith M, Beullens M, Lesage B, Krenn V, Musacchio A, Bollen M, Meyer H. Inhibitor-3 ensures bipolar mitotic spindle attachment by limiting association of SDS22 with kinetochore-bound protein phosphatase-1. EMBO J. 2014, 33(22):2704-20
Meyer HH, Bug M, Bremer S. Emerging functions of the VCP/p97 AAA-ATPase in the ubiquitin system. Nat Cell Biol. 2012 Feb 2;14(2):117-23. Review.
Ritz D, Vuk M, Kirchner P, Bug M, Schütz S, Hayer A, Bremer S, Lusk C, Baloh RH, Lee H, Glatter T, Gstaiger M, Aebersold R, Weihl CC, Meyer H. Endolysosomal sorting of ubiquitinated caveolin-1 is regulated by VCP/p97 and UBXD1 and impaired by VCP disease mutations. Nat. Cell Biol. 2011 Aug 7;13(9):1116-23.
Ramadan K, Bruderer R, Spiga F, Popp O, Baur T, Gotta M, and Meyer HH. Cdc48/p97 promotes reformation of the nucleus by extracting Aurora B kinase from chromatin. Nature 2007, 450: 1258-62.