Whorled Endoplasmic Reticulum: For Better or for Worse?

The primary function of the endoplasmic reticulum (ER) is co-translational translocation, modification, and folding of secretory, lysosomal, and transmembrane proteins. The ER is a highly dynamic organelle undergoing rapid structural and functional changes in response to intra- and extracellular signals. Accumulation within the ER of unfolded or misfolded proteins, termed ER stress, poses a lethal threat to cells. In response, cells activate a signaling cascade, called an unfolded protein response (UPR). UPR restores ER homeostasis by enhancing the organelle's folding capacity and reducing its protein load. ER stress in various cell types has often been associated with the formation of specific ER configuration, termed whorls. However, these structures appear under physiological conditions (or in models mimicking such states) and/or may be induced by natural stimuli such as high biosynthetic demand, physiological ER stress, or synthesis of cytotoxic compounds. Whorls can be stimulated in cells where they have not been previously documented, upon exposure to chemical ER stress/UPR inducers or following overexpression/mutation of ER membrane proteins. Under such conditions, cells may generate whorls to sequester and subsequently degrade aberrant, toxic, or overproduced proteins and membranes. Cells appear to utilize whorls to modulate metabolic activity, store proteins and membranes, and isolate or degrade damaged, toxic, or excessed substrates. In this context, whorls formation may have pro-survival rather than pro-death function. It seems that whorls in different organisms and cell types exhibit only phenotypic convergence, with distinct biogenesis mechanisms having evolved independently and not being universally present across all cell types.