Marius Lemberg

FM | Center for Biochemistry (UoC)

Organelle protein homeostasis

A fundamental principle of cells is their ability to monitor the integrity and functionality of their organelles. Failure or deregulation of these safeguarding systems is associated with aging as well as severe diseases such as neurodegeneration.

Research Focus

Our laboratory seeks to understand how protein homeostasis mechanisms work that control the integrity and functionality of cellular organelles. We are particularly interested in the physiological role and regulation of intramembrane proteases and transmembrane dislocases, unravelling the mechanisms to extract proteins from the membrane and coordinate their degradation by the cytosolic ubiquitin proteasome system. Our research direction will reveal a comprehensive understanding of these protein homeostasis mechanisms and shed light on potential targets for therapeutic intervention strategies to overcome the effects of protein homeostasis malfunction in disorders ranging from Parkinson’s disease to neuropathies.

Every third gene encodes a membrane protein and the majority of drug target affect membrane associated processes. Due to their biophysical properties, unique safeguarding systems for biological membranes have evolved. We study these fascinating mechanisms.

Our Goals

Our research focuses on three areas:

  • Intramembrane proteolysis and ectodomain shedding: new principles in ERAD - As the largest cellular organelle, the endoplasmic reticulum (ER) is key to many important biological processes, ranging from lipid synthesis to protein secretion to signaling. The ER-associated degradation (ERAD) pathway is important to remove misfolded and damaged proteins but also controls the quantity of many important functional proteins. The ERAD machinery forms several parallel branches that allow recognition and retrotranslocation of a heterogeneous spectrum of substrates. We and others showed that membrane proteases serve as central factors in ERAD controlling the abundance and activity of selected membrane proteins.
  • Regulated degradation of trafficking factors: tuning of secretion dynamics - Properly folded proteins are directed from the ER to the Golgi compartment via so-called COPII-coated vesicles, a process that commonly depends on cargo receptors. We aim to resolve how cargo selection is regulated at the ER exit sites. Recently, we revealed that intramembrane proteolysis tunes the activity of p24 cargo receptors, thereby controlling important plasma membrane proteins such as the innate immune receptor TLR4.
  • Interplay of mitochondrial protein homeostasis with ERAD and autophagy - Our work on mitochondria started when we discovered that the inner membrane protease PARL triggers proteasomal degradation of the serine/threonine kinase PINK1, and thereby controls this central regulator of mitophagy. More recently, we have revealed that the outer membrane dislocase Msp1 in yeast (known as ATAD1/Thorase in humans) synergies with the ERAD E3 ubiquitin ligase Doa10 to control targeting fidelity of tail-anchored proteins. Our main interest is to understand how these mitochondrial protein homeostasis mechanisms interplay with the proteasomal and lysosomal protein turnover.

Key Publications

  1. Knopf JD, Steigleder SS, Korn K, Kühnle N, Badenes M, Tauber M, Theobald SJ, Rybniker J, Adrain A, Lemberg MK. RHBDL4-triggered downregulation of COPII adaptor protein TMED7 suppresses TLR4-mediated inflammatory signaling. Nature Communications, in press.
  2. Zanotti A, Coelho JPL, Kaylani D, Singh G, Tauber M, Hitzenberger M, Avci D, Zacharias M, Russell RB, Lemberg MK*, Feige MJ*. The Human Signal Peptidase Complex Acts as a Quality Control Enzyme for Membrane Proteins. Science 378: 996-1000, 2022.
  3. 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 8: e45506, 2019.
  4. 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.
  5. 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.