PDF(Pubmed)
Abstract：
Inflammasomes comprise a group of protein complexes with fundamental roles in the induction of inflammation. Upon sensing stress factors, their assembly induces the activation and release of the pro-inflammatory cytokines interleukin (IL)-1β and -18 and a lytic type of cell death, termed pyroptosis. Recently, CARD8 has joined the group of inflammasome sensors. The carboxy-terminal part of CARD8, consisting of a function-to-find-domain (FIIND) and a caspase activation and recruitment domain (CARD), resembles that of NLR family pyrin domain containing 1 (NLRP1), which is recognized as the main inflammasome sensor in human keratinocytes. The interaction with dipeptidyl peptidases 8 and 9 (DPP8/9) represents an activation checkpoint for both sensors. CARD8 and NLRP1 are activated by viral protease activity targeting their amino-terminal region. However, CARD8 also has some unique features compared to the established inflammasome sensors. Activation of CARD8 occurs independently of the inflammasome adaptor protein apoptosis-associated speck-like protein containing a CARD (ASC), leading mainly to pyroptosis rather than the activation and secretion of pro-inflammatory cytokines. CARD8 was also shown to have anti-inflammatory and anti-apoptotic activity. It interacts with, and inhibits, several proteins involved in inflammation and cell death, such as the inflammasome sensor NLRP3, CARD-containing proteins caspase-1 and -9, nucleotide-binding oligomerization domain containing 2 (NOD2), or nuclear factor kappa B (NF-κB). Single nucleotide polymorphisms (SNPs) of CARD8, some of them occurring at high frequencies, are associated with various inflammatory diseases. The molecular mechanisms underlying the different pro- and anti-inflammatory activities of CARD8 are incompletely understood. Alternative splicing leads to the generation of multiple CARD8 protein isoforms. Although the functional properties of these isoforms are poorly characterized, there is evidence that suggests isoform-specific roles. The characterization of the functions of these isoforms, together with their cell- and disease-specific expression, might be the key to a better understanding of CARD8\'s different roles in inflammation and inflammatory diseases.
摘要：
炎性体包含一组在炎症诱导中具有基本作用的蛋白质复合物。在感知到应力因素后，它们的组装诱导促炎细胞因子白细胞介素（IL）-1β和-18的激活和释放，以及裂解型细胞死亡，称为焦亡。最近,CARD8加入了炎症体传感器组。CARD8的羧基末端部分，由功能-发现域（FIIND）和半胱天冬酶激活和募集域（CARD）组成，类似于含1的NLR家族pyrin结构域（NLRP1），它被认为是人类角质形成细胞中主要的炎性体传感器。与二肽基肽酶8和9(DPP8/9)的相互作用代表两个传感器的激活检查点。CARD8和NLRP1被靶向其氨基末端区域的病毒蛋白酶活性激活。然而,与已建立的炎症体传感器相比，CARD8还具有一些独特的功能。CARD8的激活独立于包含CARD（ASC）的炎性小体衔接蛋白凋亡相关斑点样蛋白，主要导致焦亡，而不是促炎细胞因子的激活和分泌。还显示CARD8具有抗炎和抗凋亡活性。它与，并抑制，几种参与炎症和细胞死亡的蛋白质，例如炎症体传感器NLRP3，含有CARD的蛋白质caspase-1和-9，含有核苷酸结合寡聚化结构域2（NOD2），或核因子κB（NF-κB）。CARD8的单核苷酸多态性（SNP），其中一些发生频率很高，与各种炎性疾病有关。CARD8的不同促炎和抗炎活性的分子机制尚未完全理解。选择性剪接导致产生多个CARD8蛋白同种型。尽管这些同工型的功能特性没有得到很好的表征，有证据表明同工型特异性作用.这些同工型的功能的表征，连同它们的细胞和疾病特异性表达，可能是更好地了解CARD8在炎症和炎性疾病中的不同作用的关键。
