Mutations in histones dysregulate copper homeostasis leading to defect in Sec61-dependent protein translocation...

The translocation of proteins from the cytoplasm to the endoplasmic reticulum occurs via a conserved Sec61 protein channel. Previously, we reported that mutations in histones cause downregulation of a CUP1 copper metallothionein, and copper exposure inhibits the activity of Sec61. However, the role of epigenetic dysregulation on the activity of channel is not clear. Identification of cellular factors regulating copper metabolism and Sec61 activity is needed as the dysregulation can cause human diseases. In this study, we elucidate the intricate relationship between copper homeostasis and Sec61-mediated protein translocation. Utilizing copper-sensitive yeast histone mutants exhibiting deficiencies in the expression of CUP1, we uncover a copper-specific impairment of the protein translocation process, causing a reduction in the maturation of secretory proteins. Our findings highlight the inhibitory effect of copper on both cotranslational and posttranslational protein translocations. We demonstrate that supplementation with a copper-specific chelator or amino acids such as cysteine, histidine, and reduced glutathione, zinc, and overexpression of CUP1 restores the translocation process and growth. This study, for the first time provides a functional insight on epigenetic and metabolic regulation of copper homeostasis in governing Sec61-dependent protein translocation process and may be useful to understand human disorders of copper metabolism.