The endoplasmic reticulum (ER) is a central hub for protein folding and the maintenance of cellular homeostasis. When misfolded proteins accumulate in the ER, a cellular stress response known as the unfolded protein response (UPR) is triggered to restore protein folding capacity. The transcription factor ATF6α has a central role in adapting mammalian cells to ER stress via this response, while dysregulation of ATF6α signalling has been implicated in pathophysiology of conditions such as Parkinson’s and Alzheimer’s diseases.
This has prompted efforts to identify ATF6α modulators, and in this study from the Ron lab an unbiased genome-wide CRISPR-Cas9 screen was performed in Chinese Hamster Ovary cells. This screen revealed that proteolytic processing of the ATF6α precursor to its active form was impaired in cells lacking the ER-resident Solute Carrier Family 33 Member A1 (SLC33A1). SLC33A1, also known as AT-1, has been implicated in transport of acetyl-CoA into the ER, making it available as a co-substrate for acetylation of proteins and sugars and may also transport other metabolites.
The findings in this paper findings highlight a role of SLC33A1-mediated metabolite transport in the post-ER ATF6α maturation, linking small-molecule metabolism to branch-specific signalling in the UPR. The molecular details of this dependency remain to be worked out.