TIFA,即TRAF-interacting protein with a forkhead-associated domain,是一种与TRAF(肿瘤坏死因子受体相关因子)相互作用的蛋白质,其FHA结构域允许其与TRAF6结合。TIFA在细胞信号传导中发挥着重要作用,尤其是在炎症和免疫反应的调节方面。TIFA通过与TRAF6相互作用,可以激活IkappaB激酶(IKK),进而激活NF-κB信号通路,导致炎症相关基因的表达。此外,TIFA还可以促进细胞增殖、迁移和存活,与多种癌症的发生和发展有关。
在结直肠癌中,Fusobacterium nucleatum通过释放ADP-heptose激活ALPK1/TIFA/TRAF6信号通路,进而增强NF-κB信号传导,导致炎症细胞因子IL-8的表达增加,以及抗凋亡基因BIRC3和TNFAIP3的表达上调,从而促进CRC细胞的存活和降低5-氟尿嘧啶的化疗敏感性[1]。在细菌感染中,ADP-β-D-manno-heptose(ADP-Hep)可以进入宿主细胞质,激活NF-κB信号传导,从而激活炎症反应。ADP-Hep直接结合ALPK1的N端结构域,刺激其激酶结构域,使TIFA磷酸化和激活。ADP-Hep(而不是HBP)单独或在细菌感染过程中诱导Alpk1依赖性炎症[2]。
在急性肾损伤中,TIFA表达显著上调,并定位于肾脏组织中LTL阳性细胞。TIFA的敲低可以减少线粒体损伤和细胞凋亡,表明TIFA通过激活线粒体损伤参与细胞焦亡,可能是治疗脓毒症诱导的肾损伤的治疗靶点[3]。在细菌防御系统中,T4-like噬菌体的基因tifA通过直接结合内切核糖核酸酶ToxN和RNA,形成高分子量核糖核蛋白复合物,抑制ToxN的活性,从而抑制细菌防御的ToxIN毒素-抗毒素(TA)系统[4]。
在胶质瘤中,TIFA表达上调,与胶质瘤的预后不良相关。TIFA通过E2F1促进糖酵解,从而促进胶质瘤的进展。敲低TIFA可以减少胶质瘤细胞和动物中的E2F1、GLUT1、HK2和LDHA的表达,表明TIFA可能是一种对抗胶质瘤的有益的治疗策略[5]。
在肺动脉高压中,TIFA蛋白表达与IL-1β、TNF-α、平均肺动脉压和肺血管阻力显著相关,TIFA蛋白表达可以独立预测肺动脉高压的存在,表明TIFA蛋白可能参与肺动脉高压的发病机制[6]。在肺腺癌中,TIFA表达上调,与患者生存率降低相关。敲低TIFA可以抑制细胞增殖和迁移,促进细胞周期阻滞和细胞凋亡,表明TIFA可能作为肺腺癌的预测生物标志物[7]。
在缺氧再灌注中,TIFA表达上调,与TLR4和MyD88依赖性信号传导相关。TIFA通过与TRAF6结合,促进TRAF6的寡聚化和泛素化,激活TAK1和IKK,导致NF-κB激活和HMGB1释放[8]。
在幽门螺杆菌感染中,NOD1和ALPK1/TIFA信号传导通路参与调节NF-κB依赖性反应。尽管NOD1和ALPK1/TIFA通路在调节NF-κB依赖性反应中的相对作用仍需明确,但它们可能协同而非冗余地工作[9]。
TIFA通过促进TRAF6的寡聚化和泛素化激活IKK,进而激活NF-κB信号通路,导致炎症相关基因的表达。此外,TIFA还可以促进细胞增殖、迁移和存活,与多种癌症的发生和发展有关。TIFA在结直肠癌、急性肾损伤、细菌防御、胶质瘤、肺动脉高压、肺腺癌和缺氧再灌注等多种生物学过程中发挥着重要作用,是治疗多种疾病的重要靶点。
参考文献:
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