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 and dislocases in the control of protein homeostasis


Protein degradation is an important process that ensures removal of aberrant proteins in order to adjust the cellular proteome to the functional need of cells. A fundamental challenge is to understand how membrane proteins are recognized and removed from cellular organelles. Recent studies showed that intramembrane proteolysis of transmembrane anchors provides an additional release mechanism to the previously described extraction of membrane-integral proteins by AAA-ATPases such as p97/Cdc48 or Msp1. We and others showed that intramembrane clipping of membrane proteins serves as an irreversible step in protein degradation, providing a level of regulation. A redundant set of protein dislocases and intramembrane proteases work together to control the cellular membrane proteome.


Projects in the lab focus on two aspects:

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

About one 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 protein homeostasis, 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. We and others showed that intramembrane proteases and catalytically inactive homologues, so-called pseudoproteases, serve as invariant factors in ERAD. In the lab, we use a combination of cell biological tools, biochemistry and proteomics to study the physiological function and the molecular mechanism of ER-resident proteases and pseudoproteases in protein degradation.

2.) Regulation of mitochondrial protein homeostasis

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 initially discovered that the mitochondrial rhomboid protease PARL serves as a master regulator of the serine/threonine kinase PINK1 and its influence on mitophagy. The emerging picture is that by sampling the efficiency of mitochondrial import, PARL-catalyzed removal of the PINK1 targeting signal serves as checkpoint for mitochondrial integrity. More recently, we have become interested in the mechanism and function of the outer membrane dislocase Msp1 in yeast (known as ATAD1/Thorase in humans). In an unexpected twist, we found that Msp1 synergies with the ERAD E3 ubiquitin ligase Doa10 to control targeting fidelity of tail-anchored proteins to the outer mitochondrial membrane.

Selected Publications

Original Papers


Knopf JD, Landscheidt N, Pegg CL, Schulz BL, Kühnle N, Wei CW, Huck S, Lemberg MK. Intramembrane protease RHBDL4 cleaves oligosaccharyltransferase subunits to target them for ER-associated degradation. J. Cell Sci. doi: 10.1242/jcs.243790

Dederer V, Khmelinskii A, Huhn A, Okreglak V, Knop M, Lemberg MK. Cooperation of mitochondrial and ER factors in quality control of tail-anchored proteins. eLife June 8: 8.pii: e45506 (2019)

Yücel SS, Stelzer W, Lorenzoni A, Wozny M, Langosch D, Lemberg MK. The metastable XBP1u transmembrane domain defines determinants for intramembrane proteolysis by signal peptide peptidase. Cell Rep. 26:3087-3099 (2019)

Avci D, Malchus NS, Heidasch R, Lorenz H, Richter K, Neßling M, Lemberg MK. The intramembrane protease SPP impacts morphology of the endoplasmic reticulum by triggering degradation of morphogenic proteins. J. Biol. Chem. 394: 2786-2800 (2019)

Wunderle L, Knopf JD, Kühnle N, Morle A, Hehn B, Adrain C, Strisovsky K, Freeman M, Lemberg MK. Rhomboid intramembrane protease RHBDL4 triggers ER-export and non-canonical secretion of membrane-anchored TGF-alpha. Sci. Rep. 6: 27342 (2016)

Meissner C, Lorenz H, Hehn B, Lemberg MK. Intramembrane protease PARL defines a negative regulator of PINK1- and PARK2/Parkin-dependent mitophagy. Autophagy. 11: 1484-1498 (2015)

Avci D, Fuchs S, Schrul B, Fukumori A, Breker M, Frumkin I, Chen C, Biniossek ML, Kremmer E, Schilling O, Steiner H, Schuldiner M, Lemberg MK. The yeast ER-intramembrane protease Ypf1 refines nutrient sensing by regulating transporter 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)


Reviews


Kuehnle N, Dederer V, Lemberg MK. Intramembrane proteolysis at a glance: from signalling to protein degradation. J. Cell Sci. pii: jcs217745. doi: 10.1242/jcs.217745 (2019)

Lichtenthaler SF, Lemberg MK, Fluhrer R. Proteolytic ectodomain shedding of membrane proteins in mammals-hardware, concepts, and recent developments. EMBO J. doi: 10.15252/embj. 201899456 (2018)

Avci D, Lemberg MK. Clipping or Extracting: Two ways to Membrane Protein Degradation. Trends Cell Biol. 25: 611-622 (2015)

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


Networks

Collaborative Research Centre 1036 and Research Group 2290