Ruprecht-Karls-Universität Heidelberg

Marius Lemberg
ZMBH Research Group Leader

ZMBH
Im Neuenheimer Feld 282
69120 Heidelberg, Germany
Tel.: + 49-6221 54 5889
Fax.: +49-6221 54 5893
m.lemberg@zmbh.uni-heidelberg.de

Mechanism and function of intramembrane proteases in the control of protein homeostasis

Regulated intramembrane proteolysis is an evolutionary conserved mechanism that is involved in diverse processes such as transcription control and regulated growth factor secretion. Recently we found that intramembrane proteolysis also is involved in the control of cellular membrane protein homeostasis.

Project in the lab focus on two aspects:

1.) Intramembrane proteolysis as new regulatory arm of the ERAD pathway

About a third of all mammalian proteins are synthesized in the Endoplasmic Reticulum (ER), including important cellular proteins such as cell surface receptors and channels. The ER-associated degradation (ERAD) pathway is fundamentally important to remove misfolded and damaged proteins from the ER  to maintain ER proteostasis, but also native proteins can be targeted by ERAD thereby controlling their abundance. The ERAD machinery forms several parallel pathways that allow recognition and dislocation of a heterogeneous spectrum of substrates. Recently, we showed that intramembrane proteases in yeast and humans define a unique pathway in regulated protein turnover in the ER, which we have termed ERAD-R (ER Associated Degradation-Regulatory). By studying two functionally distinct ER-resident proteases, the signal peptide peptidase (SPP) and the rhomboid protease RHBDL4, we aim to revel common principles how intramembrane proteolysis controls the abundance and integrity of membrane proteins in the eukaryotic secretory pathway.

2.) Regulation of mitophagy by the rhomboid protease PARL

Mitochondria are highly dynamic organelles required for numerous essential metabolic processes. Mitochondrial dysfunction has severe cellular effects and has been linked in humans to neurodegenerative disorders such as Parkinson’s disease. Several mutations in autosomal recessively inherited genes that lead to early onset Parkinson´s disease have been described. We study the influence of the rhomboid protease PARL on trafficking of the serine/threonine kinase and its influence on mitophagy. The emerging picture is that by sampling the efficiency of mitochondrial import, PARL-catalyzed removal of the Pink1 signal sequence serves as checkpoint for mitochondrial integrity.

Selected Publications

Original Papers

Avci D, Fuchs S, Schrul B, Fukumori A, Breker M, Frumkin I, Chen C, Biniossek ML, Kremmer E, Schilling O, Steiner H, Schuldiner M, and Lemberg MK. The yeast ER-intramembrane protease Ypf1 refines nutrient sensing by regulating tranporter abundance. Mol. Cell. 56:630-640 (2014)

Chen C, Malchus NS, Hehn B, Stelzer W, Avci D, Langosch D, Lemberg MK. Signal peptide peptidase functions in ERAD to cleave the unfolded protein response regulator XBP1u. EMBO J. 33: 2492-2506. (2014)

Fleig L, Bergbold N, Sahasrabudhe P, Geiger B, Kaltak L, Lemberg MK. Ubiquitin-Dependent Intramembrane Rhomboid Protease Promotes ERAD of Membrane Proteins. Mol Cell. 47: 558-569. (2012)

Meissner C, Lorenz H, Weihofen A, Selkoe DJ, Lemberg MK. The mitochondrial intramembrane protease PARL cleaves human Pink1 to regulate Pink1 trafficking. J. Neurochem. 117: 856-867. (2011)


Reviews

Bergbold N, Lemberg MK. Emerging role of rhomboid family proteins in mammalian biology and disease. BBA - Biomembranes. 1828: 2840-2848. (2013)

Lemberg, MK, Sampling the Membrane: Function of Rhomboid-Family Proteins. Trends Cell Biol. 23: 210-217. (2013)

Lemberg, MK, Intramembrane proteolysis in regulated protein trafficking. Traffic. 12: 1109-1118. (2011)