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

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(00)02490-9.pdf

The importance of selenium to human health

The essential trace mineral, selenium, is of fundamental importance to human health. As a constituent of selenoproteins, selenium has structural and enzymic roles, in the latter context being best-known as an antioxidant and catalyst for the production of active thyroid hormone. Selenium is needed for the proper functioning of the immune system, and appears to be a key nutrient in counteracting the development of virulence and inhibiting HIV progression to AIDS. It is required for sperm motility and may reduce the risk of miscarriage. Deficiency has been linked to adverse mood states. Findings have been equivocal in linking selenium to cardiovascular disease risk although other conditions involving oxidative stress and inflammation have shown benefits of a higher selenium status. An elevated selenium intake may be associated with reduced cancer risk. Large clinical trials are now planned to confirm or refute this hypothesis. In the context of these health effects, low or diminishing selenium status in some parts of the world, notably in some European countries, is giving cause for concern.

The importance of selenium to human health.

Protein synthesis and the folding of the newly synthesized proteins into the correct three-dimensional structure are coupled in cellular compartments of the exocytosis pathway by a process that modulates the phosphorylation level of eukaryotic initiation factor-2alpha (eIF2alpha) in response to a stress signal from the endoplasmic reticulum (ER). Activation of this process leads to reduced rates of initiation of protein translation during ER stress. Here we describe the cloning of perk, a gene encoding a type I transmembrane ER-resident protein. PERK has a lumenal domain that is similar to the ER-stress-sensing lumenal domain of the ER-resident kinase Ire1, and a cytoplasmic portion that contains a protein-kinase domain most similar to that of the known eIF2alpha kinases, PKR and HRI. ER stress increases PERK's protein-kinase activity and PERK phosphorylates eIF2alpha on serine residue 51, inhibiting translation of messenger RNA into protein. These properties implicate PERK in a signalling pathway that attenuates protein translation in response to ER stress.

Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase

Reactive oxygen species, antioxidants, and the mammalian thioredoxin system.

A new study shows that defects in SECIS-binding protein 2 (SBP2), a factor required for incorporation of selenium into proteins, produce alterations in thyroid hormone metabolism in humans but none of the other effects attributed to selenium deficiency or loss of selenoproteins. This finding suggests that SBP2 has a role in distinguishing between selenoproteins whose functions are essential and those with supporting roles in life and health.

Insights into the hierarchy of selenium incorporation.

Selenoprotein P Expression, Purification, and Immunochemical Characterization

Selenoproteins contain the unique amino acid selenocysteine (Sec), which is encoded by the triplet UGA. Since UGA also serves as a stop codon, it has been postulated that selenoprotein mRNAs are targeted for degradation by the nonsense-mediated mRNA decay pathway (NMD). Several reports have observed a hierarchy of selenoprotein mRNA expression when selenium (Se) is limiting, whereby the abundance of certain transcripts decline while others do not. We sought to investigate the role of NMD in this hierarchical response that selenoprotein mRNAs exhibit to environmental Se status. Selenoprotein mRNAs were categorized as being predicted sensitive or resistant to NMD based on the requirements held by the current model. About half of the selenoprotein transcriptome was predicted to be sensitive to NMD and showed significant changes in mRNA abundance in response to cellular Se status. The other half that was predicted to be resistant to NMD did not respond to Se status. RNA immunoprecipitation with essential NMD factor UPF1 revealed that the mRNAs that were the most sensitive to Se status were also the most enriched on UPF1 during Se deficiency. Furthermore, depletion of SMG1, the kinase responsible for UPF1 phosphorylation and NMD activation, abrogated the decline in transcript abundance of Se-responsive transcripts. Lastly, mRNA decay rates of Se-responsive transcripts were altered upon the addition of Se to resemble the slower decay rates of nonresponsive transcripts. Taken together, these results present novel evidence in support of a crucial role for the NMD pathway in regulating selenoprotein mRNA levels when Se is limiting.

/pdf/nonsense-mediated-decay-factors-are-involved-in-the-31pymfd70i.pdf

Nonsense-mediated decay factors are involved in the regulation of selenoprotein mRNA levels during selenium deficiency.

Selenium is an essential dietary micronutrient. Ingested selenium is absorbed by the intestines and transported to the liver where it is mostly metabolized to selenocysteine (Sec). Sec is then incorporated into selenoproteins, including selenoprotein P (SELENOP), which is secreted into plasma and serves as a source of selenium to other tissues of the body. Herein, we provide an overview of the biology of selenium from its absorption and distribution to selenoprotein uptake and degradation, with a particular focus on the latter. Molecular mechanisms of selenoprotein degradation include the lysosome-mediated pathway for SELENOP and endoplasmic reticulum-mediated degradation of selenoproteins via ubiquitin-activated proteasomal pathways. Ubiquitin-activated pathways targeting full-length selenoproteins include the peroxisome proliferator-activated receptor gamma-dependent pathway and substrate-dependent ubiquitination. An alternate mechanism is utilized for truncated selenoproteins, in which cullin-RING E3 ubiquitin ligase 2 targets the defective proteins for ubiquitin-proteasomal degradation. Selenoproteins, particularly SELENOP, may have their Sec residues reutilized for new selenoprotein synthesis via Sec decomposition. This review will explore these aspects in selenium biology, providing insights to knowledge gaps that remain to be uncovered.

From Selenium Absorption to Selenoprotein Degradation.

Oxidative stress and oxidized dopamine contribute to the degeneration of the nigrostriatal pathway in Parkinson's disease (PD). Selenoproteins are a family of proteins containing the element selenium in the form of the amino acid selenocysteine, and many of these proteins have antioxidant functions. We recently reported changes in expression of the selenoprotein, phospholipid hydroperoxide glutathione peroxidase GPX4 and its co-localization with neuromelanin in PD brain. To further understand the changes in GPX4 in PD, we examine here the expression of the selenium transport protein selenoprotein P (Sepp1) in postmortem Parkinson's brain tissue. Sepp1 in midbrain was expressed in neurons of the substantia nigra (SN), and expression was concentrated within the centers of Lewy bodies, the pathological hallmark of PD. As with GPX4, Sepp1 expression was significantly reduced in SN from PD subjects compared with controls, but increased relative to cell density. In putamen, Sepp1 was found in cell bodies and in dopaminergic axons and terminals, although levels of Sepp1 were not altered in PD subjects compared to controls. Expression levels of Sepp1 and GPX4 correlated strongly in the putamen of control subjects but not in the putamen of PD subjects. These findings indicate a role for Sepp1 in the nigrostriatal pathway, and suggest that local release of Sepp1 in striatum may be important for signaling and/or synthesis of other selenoproteins such as GPX4.

Marla J. Berry

Papers

Insights into the hierarchy of selenium incorporation.

Selenoprotein P Expression, Purification, and Immunochemical Characterization

Nonsense-mediated decay factors are involved in the regulation of selenoprotein mRNA levels during selenium deficiency.

From Selenium Absorption to Selenoprotein Degradation.

Changes in selenoprotein P in substantia nigra and putamen in Parkinson's disease.