RRC ID 68068
Author Ito S, Tanaka Y, Oshino R, Aiba K, Thanasegaran S, Nishio N, Isobe K.
Title GADD34 inhibits activation-induced apoptosis of macrophages through enhancement of autophagy.
Journal Sci Rep
Abstract Autophagy is a common physiological function in all eukaryotes. The process is induced by depletion of nutrients including amino acids. GADD34 is expressed following DNA damage, ER stresses and amino acid deprivation. Here, we investigated the effects of GADD34 on autophagy and cell activation in macrophages. The deprivation of tyrosine and cysteine markedly induced the expression of GADD34 in macrophages. LPS stimulation combined with tyrosine/cysteine-deprivation initially activated macrophages, but then shifted to cell death in late phase of stimulation. When LPS stimulation was combined with tyrosine/cysteine-deprivation, a deficiency of GADD34 enhanced cell activation signaling such as Src-family, Erk1/2, p38 MAPK and Akt. In the late phase of stimulation, a deficiency of GADD34 increased apoptosis more than that in wild-type macrophages. Further we found that mTOR-S6K signaling was highly enhanced in GADD34-deficient macrophages compared with wild-type cells when cells were treated by LPS combined with tyrosine/cysteine-deprivation. LC3-II was increased by LPS stimulation combined with tyrosine/cysteine-deprivation. Defective GADD34 reduced LC3-II and autophagosome formation induced by LPS-stimulation and tyrosine/cysteine-deprivation compared with that seen in wild-type macrophages. These results indicates that GADD34 enhances autophagy and suppresses apoptosis stimulated by LPS combined with amino acid deprivation through regulation of mTOR signaling pathway in macrophages.
Volume 5
Pages 8327
Published 2015-2-9
DOI 10.1038/srep08327
PII srep08327
PMID 25659802
PMC PMC4321179
MeSH Animals Apoptosis / genetics* Autophagy / genetics Caspase 3 / metabolism Cell Line Cysteine / metabolism Cysteine / pharmacology Gene Expression Gene Knockdown Techniques Humans Lipopolysaccharides / immunology Macrophage Activation / genetics* Macrophage Activation / immunology Macrophages / drug effects Macrophages / immunology Macrophages / metabolism* Mice Mice, Knockout Protein Phosphatase 1 / genetics* Protein Phosphatase 1 / metabolism Signal Transduction Sirolimus / pharmacology TOR Serine-Threonine Kinases / metabolism Tyrosine / metabolism Tyrosine / pharmacology
IF 3.998
Human and Animal Cells RAW 264(RCB0535) THP-1(RCB1189)