抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

■ Abstract Apoptosis is a genetically programmed, morphologically distinct form of cell death that can be triggered by a variety of physiological and pathological stimuli. Studies performed over the past 10 years have demonstrated that proteases play critical roles in initiation and execution of this process. The caspases, a family of cysteine-dependent aspartate-directed proteases, are prominent among the death proteases. Caspases are synthesized as relatively inactive zymogens that become activated by scaffold-mediated transactivation or by cleavage via upstream proteases in an intracellular cascade. Regulation of caspase activation and activity occurs at several different levels: ( a) Zymogen gene transcription is regulated; ( b) antiapoptotic members of the Bcl-2 family and other cellular polypeptides block proximity-induced activation of certain procaspases; and ( c) certain cellular inhibitor of apoptosis proteins (cIAPs) can bind to and inhibit active caspases. Once activated, caspases cleave a variety of intracellular polypeptides, including major structural elements of the cytoplasm and nucleus, components of the DNA repair machinery, and a number of protein kinases. Collectively, these scissions disrupt survival pathways and disassemble important architectural components of the cell, contributing to the stereotypic morphological and biochemical changes that characterize apoptotic cell death.

Mammalian caspases: structure ,a ctivation ,s ubstrates, and functions during apoptosis

The efficient functioning of the endoplasmic reticulum (ER) is essential for most cellular activities and survival. Conditions that interfere with ER function lead to the accumulation and aggregation of unfolded proteins. ER transmembrane receptors detect the onset of ER stress and initiate the unfolded protein response (UPR) to restore normal ER function. If the stress is prolonged, or the adaptive response fails, apoptotic cell death ensues. Many studies have focused on how this failure initiates apoptosis, as ER stress-induced apoptosis is implicated in the pathophysiology of several neurodegenerative and cardiovascular diseases. In this review, we examine the role of the molecules that are activated during the UPR in order to identify the molecular switch from the adaptive phase to apoptosis. We discuss how the activation of these molecules leads to the commitment of death and the mechanisms that are responsible for the final demise of the cell.

/pdf/mediators-of-endoplasmic-reticulum-stress-induced-apoptosis-18anh4a778.pdf

Mediators of endoplasmic reticulum stress-induced apoptosis.

Activation of Apoptosis Signalling Pathways by Reactive Oxygen Species

超出生体重児に対する早期デキサメサゾン投与の有用性 : National Institute of Child Health and Human Development Neonatal research Network報告 (海外誌掲載論文の和文概要とそれに対するコメント)

Faithful propagation of DNA methylation patterns during DNA replication is critical for maintaining cellular phenotypes of individual differentiated cells. Although it is well established that Uhrf1 (ubiquitin-like with PHD and ring finger domains 1; also known as Np95 and ICBP90) specifically binds to hemi-methylated DNA through its SRA (SET and RING finger associated) domain and has an essential role in maintenance of DNA methylation by recruiting Dnmt1 to hemi-methylated DNA sites, the mechanism by which Uhrf1 coordinates the maintenance of DNA methylation and DNA replication is largely unknown. Here we show that Uhrf1-dependent histone H3 ubiquitylation has a prerequisite role in the maintenance DNA methylation. Using Xenopus egg extracts, we successfully reproduce maintenance DNA methylation in vitro. Dnmt1 depletion results in a marked accumulation of Uhrf1-dependent ubiquitylation of histone H3 at lysine 23. Dnmt1 preferentially associates with ubiquitylated H3 in vitro though a region previously identified as a replication foci targeting sequence. The RING finger mutant of Uhrf1 fails to recruit Dnmt1 to DNA replication sites and maintain DNA methylation in mammalian cultured cells. Our findings represent the first evidence, to our knowledge, of the mechanistic link between DNA methylation and DNA replication through histone H3 ubiquitylation.

http://cbs.cau.edu.cn/module/download/downfile.jsp?classid=0&filename=1501051558407886717.pdf

Uhrf1-dependent H3K23 ubiquitylation couples maintenance DNA methylation and replication

Although apoptosis occurs during myogenesis, its mechanism of initiation remains unknown. In a culture model, we demonstrate activation of caspase-12, the initiator of the endoplasmic reticulum (ER) stress-specific caspase cascade, during apoptosis associated with myoblast differentiation. Induction of ER stress-responsive proteins (BiP and CHOP) was also observed in both apoptotic and differentiating cells. ATF6, but not other ER stress sensors, was specifically activated during apoptosis in myoblasts, suggesting that partial but selective activation of ER stress signaling was sufficient for induction of apoptosis. Activation of caspase-12 was also detected in developing muscle of mouse embryos and gradually disappeared later. CHOP was also transiently induced. These results suggest that specific ER stress signaling transmitted by ATF6 leads to naturally occurring apoptosis during muscle development.

https://rupress.org/jcb/article-pdf/169/4/555/1318857/jcb1694555.pdf

Endoplasmic reticulum stress signaling transmitted by ATF6 mediates apoptosis during muscle development

Translocation of Bim to the Endoplasmic Reticulum (ER) Mediates ER Stress Signaling for Activation of Caspase-12 during ER Stress-induced Apoptosis

Identification and Functions of Chondroitin Sulfate in the Milieu of Neural Stem Cells

Myoblast differentiation involves myoblast fusion followed by myofiber formation. We recently demonstrated that endoplasmic reticulum (ER) stress signaling occurs during myoblast differentiation in vivo. This signaling results in apoptosis in a subpopulation of myoblasts. In a cell culture model of myogenesis, inhibition of ER stress signaling blocked apoptosis and myoblast differentiation. To further examine the role of ER stress during myogenesis, we exposed cultured myoblasts to ER stress inducers during the transition from proliferation to differentiation. The stress inducers tunicamycin (an inhibitor of N-glycosylation in the ER) and thapsigargin (an inhibitor of ER-specific calcium ATPase) were used at doses that induce 40-50% apoptosis in myoblast cultures. Increased ER stress enhanced differentiation-associated apoptosis of myoblasts. It is likely that apoptosis induced by ER stress selectively eliminates vulnerable cells. We found that the surviving myoblast cells were even more resistant to apoptosis. Remarkably, the surviving cells efficiently differentiated into contracting myofibers that are rarely found in culture models of myogenesis. Our observations suggest that ER stress exerts a positive effect on myofiber formation, possibly mimicking the action of signals that drive apoptosis and differentiation in vivo. These results may provide important insight for developing therapies to improve myofiber formation.

Keiko Nakanishi

Papers

Uhrf1-dependent H3K23 ubiquitylation couples maintenance DNA methylation and replication

Endoplasmic reticulum stress signaling transmitted by ATF6 mediates apoptosis during muscle development

Translocation of Bim to the Endoplasmic Reticulum (ER) Mediates ER Stress Signaling for Activation of Caspase-12 during ER Stress-induced Apoptosis

Identification and Functions of Chondroitin Sulfate in the Milieu of Neural Stem Cells

Endoplasmic reticulum stress increases myofiber formation in vitro