PGRN negative regulates apoptosis through TNFR signaling pathway in chondrogenesis

摘要

BMP2 is known to activate ER stress-associated molecules, including XBP1S and ATF6.PGRN (Progranulin) was reported to be a stress-response factor in response to hypoxia and acidosis. Here we present evidences demonstrating that PGRN is also an ER stress responsive factor. PGRN expression was induced and its activation of Erk1/2 and Akt signaling enhanced in BMP2-induced chondrocyte differentiation. Besides, over-expression PGRN can inhibit, whereas knockdown PGRN by an siRNA-silencing approach increased, ER stress-mediated apoptosis in chondrogenesis induced by BMP2. Mechanistic studies indicated that PGRN/TNFR2 was critical for PGRN mediated regulation of ER stress response; the association between PGRN and TNFR2 was markedly enhanced following ER stress; More importantly, PGRN protection of ER stress induced apoptosis was abolished when TNFR2 signaling was blocked. Collectively, PGRN plays an important role in ER stress and regulates ER stress response through interacting with TNFR2. This study provides new insight into PGRN regulation of stress response and may also present PGRN as a potential molecular target for treating stress-associated disorders.