Recognition and removal of organelle damage at the endoplasmic reticulum membrane
Final Report Abstract
The human body contains a variety of organs with specialized functions. Similarly, cells in the body contain a variety of organelles, which are subcellular compartments that each carry out different sets of biochemical reactions. Cell organelles are typically enclosed by biological membranes, and selective transport of molecules across these membranes enables cells to create compartments with unique compositions and functions. The architecture of certain organelles differs substantially between cell types. Furthermore, cells can extensively remodel their organelles, for example during differentiation, stress and disease. A particularly adaptable organelle is the endoplasmic reticulum (ER), which is responsible for protein folding and lipid synthesis. When protein folding in the ER is disturbed, misfolded proteins accumulate there and cause ER stress. Cells react to this potentially lethal challenge by activating the unfolded protein response (UPR), a signalling pathway that increases the protein folding capacity of the ER and accelerates the elimination of misfolded proteins. In addition, the UPR drives ER membrane expansion, leading to an increase in ER size. This remodelling enables adaptation to new physiological situations, and failure to modify ER structure and function appropriately can lead to disorders such as diabetes and cancer. Therefore, understanding the cellular response to ER stress is important to uncover the molecular basis for certain diseases. In this project, we used baker’s yeast to investigate two previously underappreciated or unknown aspects of cellular remodelling during ER stress. First, we used Dynamic Organellar Mapping by mass spectrometry to systematically identify proteins that change their subcellular localization during ER stress. Strikingly, we found that hundreds of proteins redistributed between organelles. Some of these localization changes were expected. For instance, many proteins that fold in the ER and are then normally sent to other organelles were retained in the ER during stress, likely because they misfold. Other changes were surprising, for example the accumulation of nuclear pore complex proteins in the cytosol. These findings show that protein relocalization is a major part of cellular remodelling during ER stress. Second, we characterized a novel function of ESCRT proteins at the ER. ESCRT proteins usually shape and cut membranes. However, we observed that certain ESCRT proteins localize to the ER during stress to act as scaffolds and thus help to build a membrane contact site between the ER and the Golgi. This stress-induced contact site may facilitate the transport of sphingolipids to the Golgi and prevent their toxic accumulation in the ER. In summary, this project has provided new insight into organelle remodelling during ER stress, thus broadening our understanding of the molecular mechanisms of cell adaptation to new physiological conditions.
Publications
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Dynamic Organellar Mapping in yeast reveals extensive protein localization changes during ER stress. openRxiv.
Platzek, Anna; Schessner, Julia P.; Odehnalová, Klára; Borner, Georg H. H. & Schuck, Sebastian
