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.