细胞低氧感知与响应——2019年诺贝尔生理学或医学奖成果简析

 2019年诺贝尔生理学或医学奖颁给了William G.Kaelin、Jr、Sir Peter J.Ratcliffe、Gregg L.Semenza，以奖励他们在细胞低氧感知与适应的相关研究中所做出的开创性贡献。他们发现细胞利用了转录因子HIF-1的α亚基上的羟基化修饰来感知细胞内的氧水平，而低氧条件下未羟基化的HIF-1α会快速累积，并进入细胞核内调控上千个基因的转录。细胞低氧响应与多种人类疾病紧密相关，包括贫血症、红细胞增多症、心血管疾病、卒中以及癌症。回顾了细胞低氧响应信号通路的发现过程以及与低氧响应有关的人类疾病。     

Anti-inflammatory cyclopentenone prostaglandins are direct inhibitors of IkappaB kinase

NF-kappaB is a critical activator of genes involved in inflammation and immunity. Pro-inflammatory cytokines activate the IkappaB kinase (IKK) complex that phosphorylates the NF-kappaB inhibitors, triggering their conjugation with ubiquitin and subsequent degradation. Freed NF-kappaB dimers translocate to the nucleus and induce target genes, including the one for cyclo-oxygenase 2 (COX2), which catalyses the synthesis of pro-inflammatory prostaglandins, in particular PGE. At late stages of inflammatory episodes, however, COX2 directs the synthesis of anti-inflammatory cyclopentenone prostaglandins, suggesting a role for these molecules in the resolution of inflammation. Cyclopentenone prostaglandins have been suggested to exert anti-inflammatory activity through the activation of peroxisome proliferator-activated receptor-gamma. Here we demonstrate a novel mechanism of antiinflammatory activity which is based on the direct inhibition and modification of the IKKbeta subunit of IKK. As IKKbeta is responsible for the activation of NF-kappaB by pro-inflammatory stimuli, our findings explain how cyclopentenone prostaglandins function and can be used to improve the utility of COX2 inhibitors.     

生命的低氧适应——2019年度诺贝尔生理学或医学奖成果解析

 氧的利用和调节是高等生命赖以生存的基本条件，威廉·凯林、彼得·拉特克利夫和格雷格·塞门扎3位科学家因发现细胞感知和适应氧气供应的相关机制而获得了2019年度诺贝尔生理学或医学奖。他们发现低氧诱导因子1（hypoxia-inducible factors 1，HIF-1）广泛存在于急、慢性缺氧细胞中，是细胞适应低氧的重要转录因子。HIF-1水平受氧气含量的调节。高氧条件下，HIF-1被修饰进而降解；低氧条件下，HIF-1不被降解，并通过转录调节引起促红细胞生成素等低氧相关基因的表达。本文通过介绍HIF-1的发现和基本分子机制，探讨其在临床中的应用价值。     

Epithelial-cell-intrinsic IKK-beta expression regulates intestinal immune homeostasis

Intestinal epithelial cells (IECs) provide a primary physical barrier against commensal and pathogenic microorganisms in the gastrointestinal (GI) tract, but the influence of IECs on the development and regulation of immunity to infection is unknown. Here we show that IEC-intrinsic IkappaB kinase (IKK)-beta-dependent gene expression is a critical regulator of responses of dendritic cells and CD4+ T cells in the GI tract. Mice with an IEC-specific deletion of IKK-beta show a reduced expression of the epithelial-cell-restricted cytokine thymic stromal lymphopoietin in the intestine and, after infection with the gut-dwelling parasite Trichuris, fail to develop a pathogen-specific CD4+ T helper type 2 (T(H)2) response and are unable to eradicate infection. Further, these animals show exacerbated production of dendritic-cell-derived interleukin-12/23p40 and tumour necrosis factor-alpha, increased levels of CD4+ T-cell-derived interferon-gamma and interleukin-17, and develop severe intestinal inflammation. Blockade of proinflammatory cytokines during Trichuris infection ablates the requirement for IKK-beta in IECs to promote CD4+ T(H)2 cell-dependent immunity, identifying an essential function for IECs in tissue-specific conditioning of dendritic cells and limiting type 1 cytokine production in the GI tract. These results indicate that the balance of IKK-beta-dependent gene expression in the intestinal epithelium is crucial in intestinal immune homeostasis by promoting mucosal immunity and limiting chronic inflammation.     

The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis.

Hypoxia-inducible factor-1 (HIF-1) has a key role in cellular responses to hypoxia, including the regulation of genes involved in energy metabolism, angiogenesis and apoptosis. The alpha subunits of HIF are rapidly degraded by the proteasome under normal conditions, but are stabilized by hypoxia. Cobaltous ions or iron chelators mimic hypoxia, indicating that the stimuli may interact through effects on a ferroprotein oxygen sensor. Here we demonstrate a critical role for the von Hippel-Lindau (VHL) tumour suppressor gene product pVHL in HIF-1 regulation. In VHL-defective cells, HIF alpha-subunits are constitutively stabilized and HIF-1 is activated. Re-expression of pVHL restored oxygen-dependent instability. pVHL and HIF alpha-subunits co-immunoprecipitate, and pVHL is present in the hypoxic HIF-1 DNA-binding complex. In cells exposed to iron chelation or cobaltous ions, HIF-1 is dissociated from pVHL. These findings indicate that the interaction between HIF-1 and pVHL is iron dependent, and that it is necessary for the oxygen-dependent degradation of HIF alpha-subunits. Thus, constitutive HIF-1 activation may underlie the angiogenic phenotype of VHL-associated tumours. The pVHL/HIF-1 interaction provides a new focus for understanding cellular oxygen sensing.