Groupleader: Sebastian Schuck

Organelle Homeostasis
 

Biogenesis and Degradation of the Endoplasmic Reticulum

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



Figure 2. ER membrane expansion in human cells. Tissue culture cells expressing RFP-KDEL to highlight the ER. Cells exposed to ER stress convert their tubular ER network into sheet-like ER.

ER-phagy

Autophagy (cellular self-eating) is another response to ER stress. Upon stress, cells turn on selective autophagy of the ER, which can occur by macroautophagy and microautophagy. We have explored micro-ER-phagy, which in yeast involves a spectacular ER restructuring that gives rise to multilamellar whorls. These whorls are then sent to the lysosome for degradation (Figure 3). We have shown that micro-ER-phagy does not require the well-known core autophagy machinery but depends on ESCRT proteins (Schäfer et al., 2020). Through micro-ER-phagy, cells may sacrifice parts of their ER to destroy protein aggregates. Moreover, when stress has been resolved, micro-ER-phagy can downsize the ER and reverse organelle expansion. In this way, the UPR and ER-phagy work together to refold or degrade damaged proteins, and to expand or shrink the ER as needed. Hence, ER-phagy helps to maintain ER homeostasis and may be relevant for diseases related to ER function, such as cancer and diabetes.

Figure 3. Correlative light and electron microscopy of micro-ER-phagy in yeast. Micro-ER-phagy can be triggered by expression of an artificial transmembrane protein called 'ER-phagy inducer'. 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 4. 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).