IKBKG 缺陷导致伴有免疫缺陷的无汗性外胚层发育异常（EDA-ID）（通过 TLR）
中文名称
通路描述
许多信号通路依赖于核因子 kappa B（NFkB）的激活，这对于应对各种刺激（如炎症细胞因子、微生物产物或各种形式的压力）时诱导适当的细胞功能至关重要。NFkB 转录因子家族在细胞质中由抑制 kappa B（IkB）家族成员保持无活性。经典的 NFkB 激活依赖于 IkB 被 I kappa B 激酶（IKK）复合物磷酸化，该复合物包含两个催化亚基（IKK alpha、IKK beta）和一个调节亚基（NFkB 必需调节因子，NEMO 或 IKBKG）。IkB 的磷酸化导致 K48 连接泛素化及泛素 - 蛋白酶体降解，从而允许 NFkB 因子转位至细胞核，在那里它可以激活参与免疫和炎症反应、细胞粘附、生长控制以及抗凋亡的基因转录。IKBKG 由 X 连锁基因编码。该基因的纯合缺失在单倍体雄性中是致死的，而假合型等位基因通常导致免疫缺陷和发育缺陷谱系广泛的临床表型（Döffinger R 等，2001；Hanson EP 等，2008）。人类中已报道了几种影响 IKBKG 的突变类别（Döffinger R 等，2001；Vinolo E 等，2006；Fusko F 等，2008）。这些突变的第一类涉及假合型突变，通常涉及锌指结构域及其邻近的 C 端区域，导致男性患无汗性外胚层发育异常伴免疫缺陷（HED-ID）。第二类涉及假合型突变，导致女性患无色素性斑疹（IP），通常导致男性产前死亡（Aradhya S 等，2001；Fusco F 等，2004）。第三类涉及假合型突变，涉及终止密码子，导致男性患无汗性外胚层发育异常伴免疫缺陷（EDA-ID）、骨硬化症和淋巴水肿（OL-EDA-ID）（Döffinger R 等，2001）。此外，一些 IKBKG 基因缺陷的患者可能仅发生免疫缺陷而无外胚层发育异常（Orange JS 等，2004）。本模块描述了几种已报道的与 EDA-ID 相关的假合型 IKBKG 突变，这些突变已被证明影响由 Toll 样受体（TLR）引发的炎症反应。
英文描述
Defensins The defensins are a family of antimicrobial cationic peptide molecules which in mammals have a characteristic beta-sheet-rich fold and framework of six disulphide-linked cysteines (Selsted & Ouellette 2005, Ganz 2003). Human defensin peptides have two subfamilies, alpha- and beta-defensins, differing in the length of peptide chain between the six cysteines and the order of disulphide bond pairing between them. A third subfamily, the theta defensins, is derived from alpha-defensins prematurely truncated by a stop codon between the third and fourth cysteine residues. The translated products are shortened to nonapeptides, covalently dimerized by disulfide linkages, and cyclized via new peptide bonds between the first and ninth residues. Humans have one pseudogene but no translated representatives of the theta class.
In solution most alpha and beta defensins are monomers but can form dimers and higher order structures.
The primary cellular sources of defensins are neutrophils, epithelial cells and intestinal Paneth cells.Those expressed in neutrophils and the gut are predominantly constitutive, while those in epithelial tissues such as skin are often inducible by proinflammatory stimuli such as LPS or TNF-alpha.
Defensins are translated as precursor polypeptides that include a typical signal peptide or prepiece that is cleaved in the Golgi body, and a propiece, cleaved by differing mechanisms to produce the mature defensin. Mature defensin peptides can be further processed by removal of individual N-terminal residues (Yang et al. 2004). This may be a mechanism to broaden the activity profile of defensins (Ghosh et al. 2002).
Defensins have direct antimicrobial effects and kill a wide range of Gram-positive and negative bacteria, fungi and some viruses. The primary antimicrobial action of defensins is permeabilization of microbial target membranes but several additional mechanisms have been suggested (Brogden 2005, Wilmes et al. 2011). Defensins and related antimicrobial peptides such as cathelicidin bridge the innate and acquired immune responses. In addition to their antimicrobial properties, cathelicidin and several defensins show receptor-mediated chemotactic activity for immune cells such as monocytes, T cells or immature DCs, induce cytokine production by monocytes and epithelial cells, modulate angiogenesis and stimulate wound healing (Yang et al. 1999, 2000, 2004, Rehaume & Hancock 2008, Yeung et al. 2011).
In solution most alpha and beta defensins are monomers but can form dimers and higher order structures.
The primary cellular sources of defensins are neutrophils, epithelial cells and intestinal Paneth cells.Those expressed in neutrophils and the gut are predominantly constitutive, while those in epithelial tissues such as skin are often inducible by proinflammatory stimuli such as LPS or TNF-alpha.
Defensins are translated as precursor polypeptides that include a typical signal peptide or prepiece that is cleaved in the Golgi body, and a propiece, cleaved by differing mechanisms to produce the mature defensin. Mature defensin peptides can be further processed by removal of individual N-terminal residues (Yang et al. 2004). This may be a mechanism to broaden the activity profile of defensins (Ghosh et al. 2002).
Defensins have direct antimicrobial effects and kill a wide range of Gram-positive and negative bacteria, fungi and some viruses. The primary antimicrobial action of defensins is permeabilization of microbial target membranes but several additional mechanisms have been suggested (Brogden 2005, Wilmes et al. 2011). Defensins and related antimicrobial peptides such as cathelicidin bridge the innate and acquired immune responses. In addition to their antimicrobial properties, cathelicidin and several defensins show receptor-mediated chemotactic activity for immune cells such as monocytes, T cells or immature DCs, induce cytokine production by monocytes and epithelial cells, modulate angiogenesis and stimulate wound healing (Yang et al. 1999, 2000, 2004, Rehaume & Hancock 2008, Yeung et al. 2011).
所含基因
38 个基因