LET-607 Regulates ER And Cytosolic Proteostatic Stress Responses In Ceanorbabditis Elegans

The coordinated regulation of stress response pathways in different organelles is critical to cell homeostasis.However,the crosstalk between different organelle stress response pathways and the physiological significance of the crosstalk are still unclear.Mammalian CREBH（cAMP responsive element binding protein 3 like 3）is an ER-bound transcription factor that regulates ER stress response.By using the model organism Caenorhabditis elegans,we found that LET-607,the worm ortholog of CREBH,regulates ER proteostatic response through the IRE-1 and PEK-1 branches of the ER unfolded protein response（UPR ER）.More intriguingly,LET-607 was also found to regulate cytosolic proteostatic response.Knockdown of LET-607 increases the expression of cytosolic heat shock proteins,enhances heat stress resistance and improves cytosolic protein aggregation,implying a crosstalk between ER and cytosolic proteostatic responses.We further showed that the ITR-1-dependent Ca²⁺signaling and two calcineurin-encoding genes,tax-6 and cnb-1,are essential for LET-607-regulated expression of heat shock proteins.In addition,LET-607 regulates cytosolic proteostatic response by downregulating genes in one-carbon cycle,which generate S-adenosylmethionine（SAMe）as a methyl donor.Reduction of SAMe further affects the expression of heat shock proteins via histone methyltransferase MET-2.These findings identify novel functions of LET-607 in proteostatic response and reveal crosstalk between ER and cytosolic stress response pathways.