Marius Lemberg

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.