We have discovered a cell cycle checkpoint that ensures that all dividing cells receive both functionally correct and spatially sufficient ER during the cell cycle using a model experimental system, yeast, S. cerevisiae. During the cell cycle, if the physical sizes and/or functional capacities of the ER are not sufficient to divide into two cells, the ER inheritance and cell division (cytokinesis) are temporally blocked until the ER functions or sizes becomes sufficient to split into two cells (Babour et al., Cell 2010). This was one of the first cell cycle checkpoints for regulating the inheritance of the ER, one of the cytoplasmic components and thus, we termed as the ER stress surveillance (ERSU) cell cycle checkpoint. Recently, we found that an early biosynthetic sphingolipid, phytosphingosine (PHS), is the activating signal for the ERSU cell cycle checkpoint (i.e. ER stress causes the increase in the cellular PHS level, initiating the ERSU checkpoint hallmark events including (1) the ER inheritance block, (2) septin re-localization, (3) SLT2 MAP Kinase activation, and (4) cytokinesis block. We will employ a variety of cell and molecular biological approaches to investigate how PHS initiates the ERSU events.



We have also discovered that ER stress in mammalian cells induces specific sphingolipids, dihydrosphingosine (DHS) and dihydroceramide (DHC). Surprisingly, we found that DHS/DHC activate ATF6, one of the components of the well-recognized Unfolded Protein Response (UPR) pathway via an unprecedented mechanism that differs from the previously described mechanism. Interestingly, DHS/DHC-induced ATF6 activates transcription responses that re-establish cellular lipid synthesis and metabolisms. This differs from transcription responses that are induced by ATF6 activated via the previously described mechanism during the ER stress. These findings suggest the presence of a distinct activation mechanism(s) and responses for specifically regulating lipid-induced demands and the significance of such mechanisms for the UPR. As the UPR pathway is involved in various human diseases such as cancer, diabetes, and heart diseases, we plan to investigate the importance of DHS/DHC-activated ATF6 in the context of these diseases. In addition, we obtained evidence that the ERSU cell cycle checkpoint is conserved in mammalian cells and thus, we are excited to dissect how various types of ER stress result in the cell cycle block in mammalian cells.




If you are interested in working on these fascinating questions and would like to know more information, please contact me via e-mail (mniwarosen@ucsd.edu).




Website:

https://biology.ucsd.edu/research/faculty/mniwarosen

(The Niwa lab website is currently under re-novation).