title: GADD34 inhibits activation-induced apoptosis of macrophages through enhancement of autophagy.
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.
authors: Department of Immunology, Nagoya University Graduate School of Medicine, 65 Turumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan.
authors: Sachiko
authors: S
authors: Ito
authors: Department of Immunology, Nagoya University Graduate School of Medicine, 65 Turumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan.
authors: Yuriko
authors: Y
authors: Tanaka
authors: Department of Immunology, Nagoya University Graduate School of Medicine, 65 Turumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan.
authors: Reina
authors: R
authors: Oshino
authors: Department of Immunology, Nagoya University Graduate School of Medicine, 65 Turumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan.
authors: Keiko
authors: K
authors: Aiba
authors: Department of Immunology, Nagoya University Graduate School of Medicine, 65 Turumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan.
authors: Suganya
authors: S
authors: Thanasegaran
authors: Department of Immunology, Nagoya University Graduate School of Medicine, 65 Turumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan.
authors: Naomi
authors: N
authors: Nishio
authors: Department of Immunology, Nagoya University Graduate School of Medicine, 65 Turumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan.
authors: Ken-ichi
authors: K
authors: Isobe
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001343:Autophagy / Q000235:genetics; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D003545:Cysteine / Q000378:metabolism / Q000494:pharmacology; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D008070:Lipopolysaccharides / Q000276:immunology; D008262:Macrophage Activation / Q000235:genetics* / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D054645:Protein Phosphatase 1 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism / Q000494:pharmacology
chemical_list: D008070:Lipopolysaccharides; D014443:Tyrosine; D058570:TOR Serine-Threonine Kinases; C513256:Ppp1r15a protein, mouse; D054645:Protein Phosphatase 1; D053148:Caspase 3; D003545:Cysteine; D020123:Sirolimus