A PATHWAY DISTINCT FROM THE MAMMALIAN UNFOLDED PROTEIN RESPONSE REGULATES EXPRESSION OF ENDOPLASMIC-RETICULUM CHAPERONES IN NONSTRESSED CELLS

The stress-induced unfolded protein response (UPR) is the only signali ng pathway known to regulate expression of genes encoding the resident endoplasmic reticulum (ER) molecular chaperones and folding enzymes, yet these genes are constitutively expressed in all cells. We have exa mined the expression of ER chaperones in several cell lines that are d ependent on a variety of cytokines for growth and survival, When the v arious cell lines were deprived of essential growth factors, mRNA leve ls of the ER chaperones BiP and GRP94 decreased dramatically. Re-stimu lation of ligand-deprived cells with the appropriate growth factor ind uced BiP and GRP94 as delayed-early response genes, Cytokine induction of BiP and GRP94 biosynthesis was not preceded by a burst of glycopro tein traffic through the ER nor accompanied by expression of the CHOP transcription factor, The glycosylation inhibitor tunicamycin potently induced expression of both ER chaperones and CHOP in ligand-deprived cells, demonstrating that the UPR pathway remains functionally intact in the absence of growth factor-mediated signaling. Therefore, basal e xpression of ER chaperones is dependent upon and regulated by a mitoge nic pathway distinct from the stress-inducible UPR cascade and this pr obably controls expression of ER chaperones and folding enzymes needed to assist protein biogenesis in the ER of normal, non-stressed cells.