AG Lemberg

Welcome to the Lemberg Lab Website
Here, you'll find information about ongoing projects, the group, open positions and how to contact us. Research in the Lab is focused on:

Mechanism and function of intramembrane proteases in physiology and molecular aging

Regulated intramembrane proteolysis is an evolutionary conserved mechanism by which membrane-anchored bioactive molecules are released from cellular membranes. In eukaryotic cells, intramembrane proteases are found in different cellular organelles ranging from the endosomal system to mitochondria. These proteases function in diverse processes such as transcription control and regulated growth factor secretion. Intramembrane proteases have also been implicated in important diseases such as Alzheimer and Parkinson.

We are interested in understanding how these mysterious proteases work on the molecular level and how they act on cellular membrane homeostasis. By combining various approaches ranging from yeast genetics, cell biology, biochemistry to bioinformatics we aim to identify their substrates and analyze their function. 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.

Our research is supported by a grant from the Baden-Wuerttemberg Stiftung.

Selected Publications

Original Papers

- 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, Menendez J, Misik A, Garcia M, Koth CM, Freeman M. Mechanism of intramembrane proteolysis investigated with purified rhomboid proteases. EMBO J. 24: 464-472. (2005)

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

Reviews

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

- Lemberg, MK, Freeman M. Cutting proteins within lipid bilayers: rhomboid structure and mechanism. Mol. Cell. 28: 930-940. (2007)

Adapted from Lemberg (Traffic, 2011)