AG Lemberg

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.) Degradation of misfolded membrane proteins in the Endoplasmic Reticulum

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 serves as an important cellular safeguard by directing incorrectly folded and unassembled proteins to the cytosolic ubiquitin protease system. A number of studies have identified key players of the ER quality control system and the ERAD dislocation apparatus, but still little is known about the molecular mechanism how proteins cross the ER membrane. An open issue regarding ERAD is the degradation of membrane integral proteins. In particular it is unclear how misfolded membrane proteins are recognized, transmembrane domains are unwound and hydrophobic stretches are extracted from the lipid bilayer. We study the function of ER-resident intramembrane proteases on ERAD.

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 Pink1 and its influence on mitophagy. The emerging picture is that by sampling the efficiency of mitochondrial Pink1 import, PARL-catalyzed removal of the Pink1 signal sequence serves as checkpoint for mitochondrial integrity.

Selected Publications

Original Papers
- 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)

- Lemberg MK, Freeman M. Functional and evolutionary implications of enhanced genomic analysis of rhomboid intramembrane proteases. Genome Res. 17: 1634-1646. (2007)

- Lemberg MK, Martoglio B. Requirements for signal peptide peptidase-catalyzed intramembrane proteolysis. Mol. Cell 10:735-744. (2002)

Reviews
- Bergbold N, Lemberg, MK. Emerging role of rhomboid family proteins in mammalian biology and disease.
BBA - Biomembranes. in press

- 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)

Adapted from Lemberg (Traffic, 2011)