Cullin3-RING ubiquitin ligases are intimately linked to the unfolded protein response of the endoplasmic reticulum

CUL3-RING ubiquitin ligases (CRL3s) are involved in various cellular processes through different Bric a brac, Tramtrack and Broad-Complex (BTB)-domain proteins. KLHL12, a BTB-domain protein, appears to play an essential role in export of large cargo molecules like procollagen from the endoplasmic reticulum (ER). It has been suggested that CRL3KLHL12 mono-ubiquitinates SEC31 and mono-ubiquitinated SEC31 increases the dimension of a COPII coat to accommodate the large cargo molecules. As we examined this model, we found that functional CRL3KLHL12 was indeed critical for the assembly of large COPII structures. Interestingly, we noticed that CRL3KLHL12 influences collagen synthesis in human skin fibroblasts (HSFs). Our results also suggest that there is a CRL3KLHL12-independent collagen secretion route in HSFs. In addition, we found that CRL3KLHL12 strongly influences levels of sensors of the unfolded protein response (UPR). Different cell lines reacted differently to CUL3 depletion with respect to UPR regulation. This cell line-dependency appears to rely on a cell line-specific BTB-domain protein(s). Consistent with this idea, depletion of a muscle-specific BTB-domain protein KLHL41 recapitulated the effects of CUL3 depletion in C2C12 myotubes in UPR regulation. Based on these results we propose that CRL3KLHL12 and CRL3KLHL41 are regulators of the UPR.