Progranulin is required for proper ER stress response and inhibits ER stress-mediated apoptosis through TNFR2.
Progranulin (PGRN) was reported to be a stress-response factor in response to hypoxia and acidosis. Here we present evidences demonstrating that PGRN is also an endoplasmic reticulum (ER) stress responsive factor: PGRN expression was induced and its activation of Erk1/2 and Akt signaling enhanced in response to ER stress; Normal ER stress response was lost in PGRN deficient cells and PGRN deficient cells became hypersusceptible to ER stress-induced apoptosis; additionally, recombinant PGRN could rescue the defects in ER-stress responses seen in PGRN deficient cells. Mechanistic studies indicated that PGRN/TNFR2 was critical for PGRN mediated regulation of ER stress response: similar to PGRN, the expression of TNFR2, but not TNFR1, was also induced in the course of ER stress; in addition, 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. In addition, the 2nd and 3rd cysteine-rich domains (CRD) in the extracellular portion of TNFR2 (CRD2CRD3), known to directly bind to PGRN, disturbed the interaction of PGRN with TNFR2, and in turn abolished PGRN-mediated activation of Erk1/2 and Akt signaling and protection against apoptosis in response to ER-stress. 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.
Department of Cell Biology and Genetics, Core Facility of Development Biology, Chongqing Medical University, Chongqing 400016, China.
Meiling
M
Li
Department of Cell Biology and Genetics, Core Facility of Development Biology, Chongqing Medical University, Chongqing 400016, China.
Yanna
Y
Liu
Department of Cell Biology and Genetics, Core Facility of Development Biology, Chongqing Medical University, Chongqing 400016, China.
Fei
F
Xia
Department of Cell Biology and Genetics, Core Facility of Development Biology, Chongqing Medical University, Chongqing 400016, China.
Zhimeng
Z
Wu
Department of Cell Biology and Genetics, Core Facility of Development Biology, Chongqing Medical University, Chongqing 400016, China.
Li
L
Deng
Laboratory of Stem Cells and Tissue Engineering, Chongqing Medical University, Chongqing 400016, China.
Rong
R
Jiang
Department of Cell Biology and Genetics, Core Facility of Development Biology, Chongqing Medical University, Chongqing 400016, China. Electronic address: guo.fengjin@gmail.com.
Feng-Jin
FJ
Guo
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D000077155:Granulins; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D000077153:Progranulins; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000096:biosynthesis; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D015854:Up-Regulation
D000077155:Granulins; C120204:Grn protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases
Apoptosis; Endoplasmic reticulum stress; PGRN; TNF receptor; UPR