Calnexin controls the STAT3-mediated transcriptional response to EGF.
Calnexin 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.
Global Health Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Station 19, 1015 Lausanne, Switzerland.
Asvin K K
AK
Lakkaraju
F Gisou
FG
van der Goot
D000595:Amino Acid Sequence; D037281:Calnexin / Q000737:chemistry / Q000378:metabolism*; D053181:Caspase 8 / Q000378:metabolism; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D018832:Molecular Chaperones / Q000378:metabolism; D050828:Protein Inhibitors of Activated STAT / Q000378:metabolism; D017434:Protein Structure, Tertiary; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D016415:Sequence Alignment; D015398:Signal Transduction; D014158:Transcription, Genetic
D018832:Molecular Chaperones; C484745:PIAS3 protein, human; D050828:Protein Inhibitors of Activated STAT; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D037281:Calnexin; C512478:EGFR protein, human; D066246:ErbB Receptors; D053181:Caspase 8