Megakaryocyte maturation involves activation of the IRE1α-dependent adaptive unfolded protein response

Abstract

AbstractEndoplasmic reticulum stress triggers the unfolded protein response (UPR) to promote cell survival or apoptosis. Transient endoplasmic reticulum stress activation has been reported to trigger megakaryocyte production, and UPR activation has been reported as a feature of megakaryocytic cancers. However, the role of UPR signaling in megakaryocyte biology is not fully understood. We studied the involvement of UPR in human megakaryocytic differentiation using PMA (phorbol 12-myristate 13-acetate)-induced maturation of megakaryoblastic cell lines and thrombopoietin-induced differentiation of human peripheral blood-derived hematopoietic stem cells. Our results demonstrate that an adaptive UPR mediated by IRE1α (inositol-requiring enzyme 1α) endonuclease activity is required for megakaryocyte differentiation. Differentiation did not alter the response to the canonical endoplasmic reticulum stressors DTT or thapsigargin. However, thapsigargin, but not DTT, inhibited differentiation, consistent with the involvement of Ca2+signaling in megakaryocyte differentiation.