Herp stabilizes neuronal Ca2+ homeostasis and mitochondrial function during endoplasmic reticulum stress.
In response to endoplasmic reticulum (ER) stress, cells launch homeostatic and protective responses, but can also activate cell death cascades. A 54 kDa integral ER membrane protein called Herp was identified as a stress-responsive protein in non-neuronal cells. We report that Herp is present in neurons in the developing and adult brain, and that it is regulated in neurons by ER stress; sublethal levels of ER stress increase Herp levels, whereas higher doses decrease Herp levels and induce apoptosis. The decrease in Herp protein levels following a lethal ER stress occurs prior to mitochondrial dysfunction and cell death, and is mediated by caspases which generate a 30-kDa proteolytic Herp fragment. Mutagenesis of the caspase cleavage site in Herp enhances its neuroprotective function during ER stress. While suppression of Herp induction by RNA interference sensitizes neural cells to apoptosis induced by ER stress, overexpression of Herp promotes survival by a mechanism involving stabilization of ER Ca(2+) levels, preservation of mitochondrial function and suppression of caspase 3 activation. ER stress-induced activation of JNK/c-Jun and caspase 12 are reduced by Herp, whereas induction of major ER chaperones is unaffected. Herp prevents ER Ca(2+) overload under conditions of ER stress and agonist-induced ER Ca(2+) release is attenuated by Herp suggesting a role for Herp in regulating neuronal Ca(2+) signaling. By stabilizing ER Ca(2+) homeostasis and mitochondrial functions, Herp serves a neuroprotective function under conditions of ER stress.
Chan
Sic L
SL
Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Gerontology Research Center, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA. chanst@grc.nia.nih.gov
Fu
Weiming
W
Zhang
Peisu
P
Cheng
Aiwu
A
Lee
Jaewon
J
Kokame
Koichi
K
Mattson
Mark P
MP
D016229:Amyloid beta-Peptides / Q000737:chemistry; D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D053454:Caspase 12; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D016923:Cell Death; D002462:Cell Membrane / Q000378:metabolism*; D045304:Cytochromes c / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D004789:Enzyme Activation; D048031:JNK Mitogen-Activated Protein Kinases; D008565:Membrane Proteins / Q000737:chemistry* / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016296:Mutagenesis; D009474:Neurons / Q000378:metabolism*; D016716:PC12 Cells; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D012313:RNA / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013347:Subcellular Fractions / Q000378:metabolism; D013997:Time Factors; D014162:Transfection
D016229:Amyloid beta-Peptides; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D012313:RNA; D045304:Cytochromes c; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; C506443:Casp12 protein, rat; C505410:Casp3 protein, rat; D053454:Caspase 12; D053148:Caspase 3; D020169:Caspases; D002118:Calcium