本日は「Reduction of endoplasmic reticulum Ca2+ levels favors plasma membrane surface exposure of calreticulin (小胞体Ca2+レベルの低下はカルレティキュリンの膜表面露出を促進する)」という論文で、フランス Centre de Recherche des Cordeliers の Dr. G Kroemer のグループ(どういったラボ?→*1)による研究。(論文サイトへのlink→*2)
本日は「Potassium-induced structural changes of the endoplasmic reticulum in pyramidal neurons in murine organotypic hippocampal slices. (マウス海馬のスライスにおける錐体ニューロン内ERのKCl刺激による構造変化。)」という論文で、スウェーデン Laboratory for Experimental Brain Research, Department of Clinical Sciences Lund, Lund University の Håkan Toresson のグループ(どういったラボ?→*1)による研究。(論文サイトへのlink→*2)
本日は「p53 at the endoplasmic reticulum regulates apoptosis in a Ca2+-dependent manner (小胞体のp53はCa2+依存的にアポトーシスを制御する)」という論文で、イタリア Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, University of Ferrara の Paolo Pinton のグループ(どういったラボ?→*1)による研究。(論文サイトへのlink→*2)
The tumor suppressor p53 is a key protein in preventing cell transformation and tumor progression. Activated by a variety of stimuli, p53 regulates cell-cycle arrest and apoptosis. Along with its well-documented transcriptional control over cell-death programs within the nucleus, p53 exerts crucial although still poorly understood functions in the cytoplasm, directly modulating the apoptotic response at the mitochondrial level. Calcium (Ca2+) transfer between the endoplasmic reticulum (ER) and mitochondria represents a critical signal in the induction of apoptosis. However, the mechanism controlling this flux in response to stress stimuli remains largely unknown. Here we show that, in the cytoplasm, WT p53 localizes at the ER and at specialized contact domains between the ER and mitochondria (mitochondria-associated membranes). We demonstrate that, upon stress stimuli, WT p53 accumulates at these sites and modulates Ca2+ homeostasis. Mechanistically, upon activation, WT p53 directly binds to the sarco/ER Ca2+-ATPase (SERCA) pump at the ER, changing its oxidative state and thus leading to an increased Ca2+ load, followed by an enhanced transfer to mitochondria. The consequent mitochondrial Ca2+ overload causes in turn alterations in the morphology of this organelle and induction of apoptosis. Pharmacological inactivation of WT p53 or naturally occurring p53 missense mutants inhibits SERCA pump activity at the ER, leading to a reduction of the Ca2+ signaling from the ER to mitochondria. These findings define a critical nonnuclear function of p53 in regulating Ca2+ signal-dependent apoptosis.
*1:このグループはCa2+のダイナミクスを分子細胞レベルで研究しているラボのようです。 --The laboratory has developed avouched competences in the studying of calcium (Ca2+) homeostasis, in particular using recombinant proteins such as the Ca2+-sensitive photoprotein aequorins, the mutants of Green Fluorescent Protein (GFP) and different chemical probes. Moreover, we operate as center for cell imaging with particular interest in mitochondrial and Protein Kinase C (PKC) imaging. Finally, the group is involved in the study of adipocytes differentiation of stem cells population derived from different adult tissues. -- http://sm.unife.it/it/ricerca-e-terza-missione/ricerca-1/ambiti/signaltransductionlab/researchより。
結論から言うと、 DNA 損傷によりp53 が活性化すると、REEP1/2 の発現上昇による滑面小胞体の増加、EI24 の発現上昇によるER-ミトコンドリア間MCS の形成促進が誘導される。その結果ER からミトコンドリアへのCa2+移動が促進されアポトーシスが誘導される、ということを示した論文。
本日は「DNA damage triggers tubular endoplasmic reticulum extension to promote apoptosis by facilitating ER-mitochondria signaling (DNA損傷は滑面小胞体の伸長を誘発し、ER-ミトコンドリアシグナル伝達を促進してアポトーシスを促進する。)」という論文で、中国 Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, State Key Laboratory of Membrane Biology, College of Life Sciences, Peking University(北京大学) の Jianguo Chen のグループによる研究。(論文サイトへのlink→*1)
本日は「p180 Promotes the Ribosome-Independent Localization of a Subset of mRNA to the Endoplasmic Reticulum (p180はリボソームに依存しない小胞体へのmRNAの局在化を促進する)」という論文で、カナダ Department of Biochemistry, University of Toronto の Andrea Daga のグループ(どういったラボ?→*1)による研究。(論文サイトへのlink→*2)
In metazoans, the majority of mRNAs coding for secreted and membrane-bound proteins are translated on the surface of the endoplasmic reticulum (ER). Although the targeting of these transcripts to the surface of the ER can be mediated by the translation of a signal sequence and their maintenance is mediated by interactions between the ribosome and the translocon, it is becoming increasingly clear that additional ER-localization pathways exist. Here we demonstrate that many of these mRNAs can be targeted to, and remain associated with, the ER independently of ribosomes and translation. Using a mass spectrometry analysis of proteins that associate with ER-bound polysomes, we identified putative mRNA receptors that may mediate this alternative mechanism, including p180, an abundant, positively charged membrane-bound protein. We demonstrate that p180 over-expression can enhance the association of generic mRNAs with the ER. We then show that p180 contains a lysine-rich region that can directly interact with RNA in vitro. Finally, we demonstrate that p180 is required for the efficient ER-anchoring of bulk poly(A) and of certain transcripts, such as placental alkaline phosphatase and calreticulin, to the ER. In summary, we provide, to our knowledge, the first mechanistic details for an alternative pathway to target and maintain mRNA at the ER. It is likely that this alternative pathway not only enhances the fidelity of protein sorting, but also localizes mRNAs to various subdomains of the ER and thus contributes to cellular organization.
*1:このグループはmRNAに主眼をおいていて、mRNAの核外への輸送, 適切なmRNAの局在, ERにおける翻訳と細胞質における翻訳の違い、等を研究しているラボのようです。 --1) How are mRNAs exported from the nucleus? 2) How are mRNAs localized to their proper subcellular destination, such as the endoplasmic reticulum? 3) How does mRNA translation in the cytosol differ from translation on the endoplasmic reticulum? -- http://biochemistry.utoronto.ca/person/alexander-f-palazzo/より。このトロント大学のbiochemistryのwebページがカッコよい!
本日は「Dynamic constriction and fission of endoplasmic reticulum membranes by reticulon (レティキュロンによる小胞体膜の動的収縮と分裂)」という論文で、イタリア Scientific Institute, IRCCS E. Medea, Laboratory of Molecular Biology の Andrea Daga のグループ(どういったラボ?→*1)による研究。(論文サイトへのlink→*2)
The endoplasmic reticulum (ER) is a continuous cell-wide membrane network. Network formation has been associated with proteins producing membrane curvature and fusion, such as reticulons and atlastin. Regulated network fragmentation, occurring in different physiological contexts, is less understood. Here we find that the ER has an embedded fragmentation mechanism based upon the ability of reticulon to produce fission of elongating network branches. In Drosophila, Rtnl1-facilitated fission is counterbalanced by atlastin-driven fusion, with the prevalence of Rtnl1 leading to ER fragmentation. Ectopic expression of Drosophila reticulon in COS-7 cells reveals individual fission events in dynamic ER tubules. Consistently, in vitro analyses show that reticulon produces velocity-dependent constriction of lipid nanotubes leading to stochastic fission via a hemifission mechanism. Fission occurs at elongation rates and pulling force ranges intrinsic to the ER, thus suggesting a principle whereby the dynamic balance between fusion and fission controlling organelle morphology depends on membrane motility.