Stem cell proliferation in the C. elegans germline is primarily supported by the GLP-1/Notch signalling pathway. We have found that induction of the Unfolded Protein Response inhibits GLP-1/Notch signalling levels thereby resulting in suppression of stem cell proliferation. We first focussed on a Derlin (Degradation in the Endoplasmic Reticulum) protein, called
cup-2, known to be involved in the ER-Associated degradation pathway of protein quality control. Loss of
cup-2 has previously been shown to lead to ER stress and activate the Unfolded Protein Response, a pathway that helps protect cells against ER stress (Ye et al. 2004 & Schaheen et al. 2009). We found that loss of
cup-2 suppressed several Notch-dependent germline tumours but could not suppress Notch-independent germline tumours. Loss of the closely related Derlin gene,
der-2, was also able to suppress a Notch-dependent tumour and loss of both
cup-2 and
der-2 additively suppressed a Notch-dependent tumour. Using a readout for Notch signalling, we found that the level of Notch signalling in
cup-2(0);
glp-1(gf) germlines was reduced to nearly wild-type levels in contrast to the higher levels seen in the
glp-1(gf) background. Since Derlin proteins are involved in protein quality control, and the loss of their activity induces ER stress, we asked whether chemical induction of ER stress could also suppress Notch-dependent tumours. We found that induction of ER stress using Dithiothreitol (DTT) or Thapsigargin was able to suppress Notch-dependent tumours but could not suppress a Notch-independent tumour. We further found that
cup-2 suppression is dependent on XBP-1, a key player in the Unfolded Protein Response pathway. Therefore, we conclude that activation of the Unfolded Protein Response by inducing ER stress, reduces GLP-1/Notch signalling levels in the germline. This work highlights the importance of protein quality control mechanisms in promoting GLP-1/Notch signalling in the germline. References Ye Y, Shibata Y, Yun C, et al (2004) A membrane protein complex mediates retro- translocation from the ER lumen into the cytosol. Schaheen B, Dang H, Fares H (2009) Derlin-dependent accumulation of integral membrane proteins at cell surfaces. J Cell Sci 122:2228-2239. doi: 10.1242/jcs.048892