Forschungsgruppen
Forschung
Organelle Homeostasis
Biogenesis and Degradation of the Endoplasmic Reticulum
We want to elucidate how cells ensure homeostasis of the endoplasmic reticulum (ER). We are asking questions such as: How do cells adjust ER size to physiological demand? How do cells control ER shape to optimally support its functions? How do cells eliminate ER damage? Using budding yeast and human cells, we focus on ER membrane biogenesis, which enables organelle expansion and remodelling and helps to prevent an accumulation of misfolded proteins. Two other processes we have investigated are ER-phagy, which mediates autophagic organelle degradation, and SHRED, which regulates proteasomal degradation of misfolded cytosolic and ER membrane proteins.
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 triggers massive expansion of the ER membrane, both in yeast (Figure 1) and in human cells (Figure 2). We have identified genes required for ER membrane expansion and determined how they regulate lipid metabolism (Papagiannidis, Bircham et al, 2021). Furthermore, we have found that protein relocalization is a major aspect of cellular reorganization in response to ER stress (Platzek et al, 2025).
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. Besides the regulation of ER size, we are keen to understand how cells control ER shape, including the proportion of ER tubules and sheets, the generation of ER stacks and the formation of ER whorls.
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.
SHRED
Protein folding is error-prone, especially during stress. Cells possess elaborate quality control machinery, including numerous chaperones and ubiquitin ligases, to promote proper folding and degrade folding failures. Stress responses like the UPR tune quality control to current demand. We have uncovered a novel stress response pathway termed SHRED, for stress-induced homeostatically regulated protein degradation (Figure 4; Szoradi et al, 2018; Peters, Kanngießer et al, 2025). SHRED is activated when stress stimulates transcription of the Roq1 gene. The Roq1 protein is cleaved by the protease Ynm3. Truncated Roq1 then binds to the ubiquitin ligase Ubr1 as a pseudosubstrate, reprograms Ubr1's substrate specificity and directs it towards misfolded cytosolic and ER membrane proteins. The resulting more stringent quality control enhances stress resistance. Deteriorating protein quality control during aging is a key factor for the onset of neurodegenerative diseases such as Alzheimer’s. Moreover, cancer cells suffer from chronic folding stress and depend on heightened quality control for survival.
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).
Selected publications
Platzek A, Odehnalova K, Schessner JP, Borner GH, Schuck S (2025) Dynamic Organellar Mapping in yeast reveals extensive protein localization changes during ER stress. Nature Communications (abstract)
Peters N*, Kanngießer S*, Pajonk O, Salazar Claros R, Hubbe P, Mogk A, Schuck S (2025) Reprograming of the ubiquitin ligase Ubr1 by intrinsically disordered Roq1 through cooperating multifunctional motifs. EMBO Journal (abstract)
Papagiannidis D*, Bircham PW*, Lüchterborg C, Pajonk O, Ruffini G, Brügger B, Schuck S (2021) Ice2 promotes ER membrane biogenesis in yeast by inhibiting the conserved lipin phosphatase complex. EMBO Journal (abstract)
Schäfer JA, Schessner JP, Bircham PW, Tsuji T, Funaya C, Pajonk O, Schaeff K, Ruffini G, Papagiannidis D, Knop M, Fujimoto T, Schuck S (2020) ESCRT machinery mediates selective microautophagy of endoplasmic reticulum in yeast. EMBO Journal (abstract)
Szoradi T, Schaeff K, Garcia-Rivera EM, Itzhak DN, Schmidt RM, Bircham PW, Leiss K, Diaz-Miyar J, Chen VK, Muzzey D, Borner GH, Schuck S (2018) SHRED is a regulatory cascade that reprograms Ubr1 substrate specificity for enhanced protein quality control during stress. Molecular Cell (abstract)
