Tuning and assimilation of endoplasmic reticulum (ER) content in each cell of the human body is an essential part of organismal homeostasis and adaptation to stress. As such, the lysosomal turnover of ER (reticulophagy) needs to be regulated in a spatio-temporal as well as cell-type specific manner. We recently identified CSNK2/CK2 (casein kinase 2) as the enzyme that phosphorylates the reticulophagy receptors RETREG1/FAM134B and RETREG3/FAM134C and regulates their activity. Phosphorylation of the receptors is a prerequisite for their subsequent functional ubiquitination and the formation of high-density clusters, presumably representing active macroautophagy/autophagy sites at the ER membrane. Consistently, treatment with kinase inhibitor SGC-CK2-1, knockdown of endogenous CSNK2, or mutation of respective phospho-sites prevents ubiquitination, the formation of high-density clusters as well as reticulophagy flux. We hypothesize that CSNK2 has a broader impact on ER and Golgi content in a cell-type and context-specific manner by orchestrating the activity of several autophagy receptors and potentially also factors of the ER-associated protein degradation pathway.
Keywords: ER-phagy; kinase; kinase signaling; organelle turnover; phosphorylation; ubiquitination.