Ca2+-driven PDIA6 phase separation to ensure proinsulin quality control

Ca2+-driven PDIA6 phase separation to ensure proinsulin quality control Abstract The endoplasmic reticulum (ER) plays key roles in protein quality control1,2 and dynamic Ca2+ storage3,4 in eukaryotic cells. However, the protein homeostasis (proteostasis) system that regulates these ER functions is still incompletely characterised. Previous study revealed the importance of oligomerization in the function PDIA1, an ER-resident disulfide isomerase and molecular chaperone, regulates oligomeric states in accordance with client folding5. This result suggests that at least some of the 20 members of other PDI family may undergo regulated self-assembly in order to optimally function. Here, we show that Ca2+ triggers the phase separation of PDIA6 into liquid-like condensates. In contrast to the condensation mechanism observed for proteins containing low-complexity domains, our results indicate that transient but specific electrostatic interactions occur between the first and the third folded thioredoxin-like domains of PDIA6. We further show that the Ca2+-driven condensation of PDIA6 recruits PDIA3 and proinsulin, thus increasing their local concentrations. This process results in the 30-fold enhancement of proinsulin folding and in the inhibition of proinsulin aggregation. Our findings shed light on a condensation-driven Ca2+-mediated proteostasis cascade in the ER by revealing how the efficiency of the protein folding process can be enhanced within quality control granules. Competing Interest Statement Eiichiro Mori is a CEO of molmir, Inc. Data availability Subject Area - Biochemistry (17728) - Bioengineering (13921) - Bioinformatics (42047) - Biophysics (21490) - Cancer Biology (18637) - Cell Biology (25555) - Clinical Trials (138) - Developmental Biology (13403) - Ecology (19942) - Epidemiology (2067) - Evolutionary Biology (24368) - Genetics (15625) - Genomics (22549) - Immunology (17764) - Microbiology (40475) - Molecular Biology (17208) - Neuroscience (88761) - Paleontology (667) - Pathology (2842) - Pharmacology and Toxicology (4834) - Physiology (7659) - Plant Biology (15175) - Synthetic Biology (4304) - Systems Biology (9835) - Zoology (2272)