防御素
中文名称
通路描述
防御素是一类具有β-折叠丰富折叠和六硫醚键连接的半胱氨酸框架的抗菌阳离子肽分子。人类防御素分为α-防御素和β-防御素两个亚族，以及源自α-防御素提前截短产生的θ-防御素。在溶液中，α和β防御素主要以单体形式存在，但可形成二聚体及更高阶结构。主要细胞来源为中性粒细胞、上皮细胞和肠道潘氏细胞。中性粒细胞和肠道表达的防御素主要为固有免疫，而皮肤等上皮组织的表达则常由促炎刺激如LPS或TNF-α诱导。防御素翻译为包含信号肽和加工肽的前体多肽，经信号肽和加工肽切除后形成成熟防御素。成熟防御素可进一步通过切除N端残基进行加工，以拓宽其活性谱。防御素具有直接的抗菌作用，可杀死革兰氏阳性和阴性细菌、真菌及部分病毒。其主要的抗菌机制是微生物靶标膜的通透性增加，此外还有多种机制被提出。防御素及相关抗菌肽如cathelicidin在先天免疫和获得性免疫之间起桥梁作用，除了抗菌特性外，还能诱导免疫细胞趋化、促炎因子产生、调节血管生成及促进伤口愈合。
英文描述
Activated NOTCH1 Transmits Signal to the Nucleus Mature NOTCH1 heterodimer on the cell surface is activated by one of its ligands: DLL1 (Cordle et al. 2008, Jarriault et al. 1998), DLL4 (Benedito et al. 2009), JAG1 (Li et al. 1998, Benedito et al. 2009) or JAG2 (Luo et al. 1997, Shimizu et al. 2000), expressed in trans on a neighboring cell. Thus, a ligand-expressing cell is a signal-sending cell, while the NOTCH1 expressing cell is a signal-receiving cell. If NOTCH1 has undergone Fringe modification in the Golgi, it is preferentially activated by Delta ligands (Yang et al. 2005), DLL1 and DLL4.
Upon binding to NOTCH1 on a neighboring cell, NOTCH ligands are ubiquitinated by Mindbomb (MIB1 and MIB2) and/or Neuralized (NEURL and NEURL1B) E3 ubiquitin ligases and endocytosed (Koo et al. 2007, Koo et al. 2005, Itoh et al. 2003, Lai et al. 2001, Koutelou et al. 2008, Song et al. 2006). Endocytosis of ubiquitinated ligands is thought to mechanically stretch the bound NOTCH1 receptor, exposing a cleavage site S2 that is recognized by ADAM10 and/or ADAM17 metalloprotease (van Tetering et al. 2009, Brou et al. 2000, Hartmann et al. 2002, Pan et al. 1997). S2 cleavage of NOTCH1 produces the NEXT1 fragment which is further cleaved at an S3 cleavage site by the gamma-secretase complex, resulting in release of the NOTCH1 intracellular domain (NICD1) into the cytosol (de Strooper et al. 1999, Schroeter et al. 1998, Huppert et al. 2000). NICD1 produced by activation of NOTCH1 in response to in trans presented Delta and Jagged ligands (DLL/JAG) traffics to the nucleus where it acts as a transcription regulator.
NOTCH1 signaling can also be activated by ligands other than DLL1, DLL4, JAG1 and JAG2. CNTN1 (Contactin-1), transiently expressed during central and peripheral nervous system development, activates NOTCH1 and NOTCH2 in trans, promoting oligodendrocyte maturation and myelination (Hu et al. 2003). DNER (Delta and Notch-like epidermal growth factor-related receptor) is a transmembrane protein specifically expressed in dendrites and cell bodies of postmitotic neurons. Activation of NOTCH1 by DNER in trans may play an important role in development of the central nervous system by influencing differentiation of astrocytes (Eiraku et al. 2005). Activation of NOTCH1 by both CNTN1 and DNER is Deltex (DTX)-dependent and results in gamma-secretase mediated release of NICD1. Three members of the Deltex protein family: DTX1, DTX2 and DTX4 possess a domain involved in binding cdc10/ankyrin repeats of NOTCH. DTX proteins are considered as positive regulators of NOTCH signaling, although the exact mechanism has not been elucidated (Matsuno et al. 1998, Kishi et al. 2001).In addition, DTX can mediate downregulation of NOTCH signaling by recruiting non-visual beta-arrestins to NOTCH (Mukherjee et al. 2005), thereby trigerring NOTCH ubiquitination. DTX proteins are negatively regulated by ITCH (AIP4) ubiquitin ligase (Chastagner et al. 2006).
NOTCH1 signaling in the signal-receiving cell can be turned off in cis by expression of NOTCH ligands DLL/JAG (Cordle et al. 2008, Sprinzak et al. 2010), as well as DLK1 (Baladron et al. 2005, Bray et al. 2008). Formation of NOTCH1:ligand complexes in cis prevents interaction of NOTCH1 with ligands expressed in trans, resulting in the inhibition of NOTCH signaling. In the signal-sending cell, NOTCH signaling can be negatively regulated by the protein NUMB, which is asymmetrically distributed during cell division (Rhyu et al. 1994). NUMB recruits ITCH ubiquitin ligase to NOTCH1 and promotes sorting of NOTCH1 through late endosomes for degradation (McGill et al. 2009, Chastagner et al. 2008).
Upon binding to NOTCH1 on a neighboring cell, NOTCH ligands are ubiquitinated by Mindbomb (MIB1 and MIB2) and/or Neuralized (NEURL and NEURL1B) E3 ubiquitin ligases and endocytosed (Koo et al. 2007, Koo et al. 2005, Itoh et al. 2003, Lai et al. 2001, Koutelou et al. 2008, Song et al. 2006). Endocytosis of ubiquitinated ligands is thought to mechanically stretch the bound NOTCH1 receptor, exposing a cleavage site S2 that is recognized by ADAM10 and/or ADAM17 metalloprotease (van Tetering et al. 2009, Brou et al. 2000, Hartmann et al. 2002, Pan et al. 1997). S2 cleavage of NOTCH1 produces the NEXT1 fragment which is further cleaved at an S3 cleavage site by the gamma-secretase complex, resulting in release of the NOTCH1 intracellular domain (NICD1) into the cytosol (de Strooper et al. 1999, Schroeter et al. 1998, Huppert et al. 2000). NICD1 produced by activation of NOTCH1 in response to in trans presented Delta and Jagged ligands (DLL/JAG) traffics to the nucleus where it acts as a transcription regulator.
NOTCH1 signaling can also be activated by ligands other than DLL1, DLL4, JAG1 and JAG2. CNTN1 (Contactin-1), transiently expressed during central and peripheral nervous system development, activates NOTCH1 and NOTCH2 in trans, promoting oligodendrocyte maturation and myelination (Hu et al. 2003). DNER (Delta and Notch-like epidermal growth factor-related receptor) is a transmembrane protein specifically expressed in dendrites and cell bodies of postmitotic neurons. Activation of NOTCH1 by DNER in trans may play an important role in development of the central nervous system by influencing differentiation of astrocytes (Eiraku et al. 2005). Activation of NOTCH1 by both CNTN1 and DNER is Deltex (DTX)-dependent and results in gamma-secretase mediated release of NICD1. Three members of the Deltex protein family: DTX1, DTX2 and DTX4 possess a domain involved in binding cdc10/ankyrin repeats of NOTCH. DTX proteins are considered as positive regulators of NOTCH signaling, although the exact mechanism has not been elucidated (Matsuno et al. 1998, Kishi et al. 2001).In addition, DTX can mediate downregulation of NOTCH signaling by recruiting non-visual beta-arrestins to NOTCH (Mukherjee et al. 2005), thereby trigerring NOTCH ubiquitination. DTX proteins are negatively regulated by ITCH (AIP4) ubiquitin ligase (Chastagner et al. 2006).
NOTCH1 signaling in the signal-receiving cell can be turned off in cis by expression of NOTCH ligands DLL/JAG (Cordle et al. 2008, Sprinzak et al. 2010), as well as DLK1 (Baladron et al. 2005, Bray et al. 2008). Formation of NOTCH1:ligand complexes in cis prevents interaction of NOTCH1 with ligands expressed in trans, resulting in the inhibition of NOTCH signaling. In the signal-sending cell, NOTCH signaling can be negatively regulated by the protein NUMB, which is asymmetrically distributed during cell division (Rhyu et al. 1994). NUMB recruits ITCH ubiquitin ligase to NOTCH1 and promotes sorting of NOTCH1 through late endosomes for degradation (McGill et al. 2009, Chastagner et al. 2008).
所含基因
34 个基因