Groupleader: Sebastian Schuck

Organelle Homeostasis
 

Biogenesis and Degradation of the Endoplasmic Reticulum

The ER is a morphologically complex organelle with vital functions in protein folding and lipid synthesis. When the ER is unable to fold its load of newly synthesized polypeptides, misfolded proteins accumulate and cause ER stress. Misfolded proteins activate the unfolded protein response (UPR), which increases the protein folding capacity of the ER and induces ER-associated degradation. In this way, the UPR promotes the removal of misfolded proteins. Related mechanisms cooperate with the UPR to clear troublesome proteins, including proteasome biogenesis (Schmidt et al, 2019). Furthermore, the UPR triggers massive expansion of the ER membrane by activating lipid synthesis (Figure 1; Schuck et al, 2009). We have identified genes required for ER expansion and determined how they regulate lipid metabolism and ER membrane biogenesis (Papagiannidis, Bircham et al, 2021). Secretory cells, such as antibody-secreting plasma cells, need to expand the ER membrane during differentiation. Therefore, finding out how cells adjust ER size will help us understand how cells respond to stress and also how they differentiate.



Figure 1. ER membrane expansion. Yeast expressing Sec63-GFP to highlight the cytoplasmic ER (cER) and the nuclear envelope (NE). Yeast exposed to ER stress have a vastly expanded cytoplasmic ER.
 

Figure 2. Correlative light and electron microscopy of micro-ER-phagy. Micro-ER-phagy can be triggered by expression of the 'ER-phagy inducer', an artificial GFP-tagged transmembrane protein. Fluorescence images show a ring-shaped structure positive for a general ER marker and the ER-phagy inducer. The corresponding electron micrograph reveals that this structure is a large multilamellar ER whorl inside the yeast lysosome.

Figure 3. SHRED. Under non-stress conditions, the ubiquitin ligase Ubr1 degrades proteins with positively charged N-terminal residues as part of the N-degron pathway (left). Under stress conditions, Roq1 is produced, is cleaved by Ynm3 and binds to Ubr1 as a pseudosubstrate. This reprograms Ubr1 and stimulates the degradation of misfolded proteins (right).