Calnexin Controls the STAT3-Mediated Transcriptional Response to EGF

•Calnexin is cleaved by caspase-8 in response to EGF•Cleaved calnexin tail binds to PIAS3, an inhibitor of activated STAT3 in the nucleus•The calnexin fragment, through interaction with PIAS3, promotes STAT3 signaling•ER stress is sensed by calnexin and abrogates the promotion of STAT3 signaling

SummaryCalnexin is a well-characterized transmembrane chaperone involved in the folding of newly synthesized glycoproteins in the lumen of the endoplasmic reticulum (ER). Here, we reveal a previously unrecognized function of calnexin in regulating the transcriptional response downstream of epidermal growth factor receptor (EGF), the product of a well-known human oncogene. We find that cell stimulation with EGF leads to the caspase-8-dependent cleavage of the calnexin cytoplasmic domain, preferentially at ER-mitochondria interaction sites. The released fragment translocates into the nucleus, binds to PIAS3—a natural inhibitor of activated STAT3—and, thus, acts as an enhancer of the STAT3-mediated transcriptional response to EGF. Also, we reveal the unsuspected capacity of calnexin to sense ER stress and, in response, prevent the EGF-induced processing of its cytosolic domain. Thus, cells integrate the health status of the ER to determine the amplitude of their response to EGF.