CUL3-RING ubiquitin ligases (CRL3s) are involved in diverse cellular processes through over two hundred BTB-domain proteins. KLHL12, a BTB-domain protein, has been suggested to play an essential role in export of unusually 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. However, it did not directly affect collagen secretion, but instead influenced collagen synthesis in human skin fibroblasts (HSFs). These results also suggest that there is a CRL3KLHL12–independent collagen secretion route. Unexpectedly, CRL3KLHL12 strongly influenced the levels of sensors of the unfolded protein response (UPR) such as PERK and IRE1α. Interestingly, different cell lines reacted differently to CUL3 depletion. This cell-line dependency appears to rely on a cell-line specific BTB-domain protein(s) and a cell-line specific substrate(s) of the BTB-domain protein. Consistent with this idea, depletion of a muscle-specific BTB-domain protein KLHL41 recapitulated the effects of CUL3 depletion in C2C12 myotubes. Based on these results we propose that CRL3KLHL12 and CRL3KLHL41 are regulators of the UPR sensors.