GBP 介导宿主防御的调节
中文名称
通路描述
Guanylate-binding protein 1 (GBP1) 活性受到严格调节，以平衡抗菌防御和防止过度炎症。Caspase-1 (CASP1) 在 D192 处切割 GBP1，产生无活性的片段，使其失去靶向内源性沙门氏菌的能力，无法招募 caspase-4 (CASP4) 或诱导焦磷酸化。这种切割作为反馈机制，限制了感染细菌时的焦磷酸化细胞死亡，但在 Toxoplasma gondii 感染中不发生，表明存在病原体特异性调节 (Naschberger E et al., 2017; Fisch D et al., 2020)。PIM1 激酶在 Ser156 和 Thr590 处磷酸化 GBP1，Ser156 磷酸化促进其与 14-3-3Ï (SFN) 的结合，将 GBP1 滞留在细胞质中并抑制其膜结合型抗菌活性 (Fisch D et al., 2023)。GTP 结合通过变构机制破坏 PIM1:GBP1 复合物，突显 GBP1 如何整合核苷酸和磷酸化依赖性控制以精细调节宿主防御 (Persico M et al., 2015; De Donato M et al., 2012; Andreoli M et al., 2014)。
英文描述
Constitutive Signaling by NOTCH1 HD Domain Mutants The heterodimerization (HD) domain of NOTCH1, responsible for association of NOTCH1 extracellular and transmembrane regions after furin-mediated cleavage of NOTCH1 precursor, is one of the hotspots for gain-of-function NOTCH1 mutations in T-cell acute lymphoblastic leukemia (T-ALL) (Weng et al. 2004). NOTCH1 HD domain mutants are responsive to ligand binding, but the activation (through cleavage of S2 and S3 sites and release of the intracellular domain NICD1) also happens spontaneously, in the absence of DLL and JAG ligands (Malecki et al. 2006). The following NOTCH1 HD domain mutants were directly functionally studied by Malecki et al.: NOTCH1 V1576E, NOTCH1 F1592S, NOTCH1 L1593P, NOTCH1 L1596H, NOTCH1 R1598P, NOTCH1 I1616N, NOTCH1 I1616T, NOTCH1 V1676D, NOTCH1 L1678P, NOTCH1 I1680N, NOTCH1 A1701P and NOTCH1 I1718T; other frequent NOTCH1 HD domain mutants (NOTCH1 L1574P, NOTCH1 L1574Q and NOTCH1 L1600P) are assumed to behave in a similar way.
所含基因
16 个基因