Chlamydial CT441 is a PDZ domain-containing tail-specific protease that interferes with the NF-κB pathway of immune response
Chlamydial CT441 is a PDZ domain-containing tail-specific protease that interferes with the NF-κB pathway of immune response
复制标题
DOI：
10.1128/jb.00429-07
复制
发表时间：
2007-09-01
影响因子：
3.2
通讯作者：
Li, Erguang
中科院分区：
文献类型：
--
作者：
Lad, Sonya P.;Yang, Guang;Li, Erguang
衣原体是一种细菌性病原体，影响全球超过1.4亿人。沙眼衣原体引起的眼部感染是可预防失明的主要原因，而泌尿生殖道衣原体感染则会导致性传播疾病。作为专性细胞内生物体，衣原体物种已经进化出逃避宿主免疫系统的机制，包括转录因子调节因子X5和上游刺激因子1的降解，这是通过CPAF表达主要组织相容性复合体分子I和II以及通过编码的CT 441蛋白切割NF-κ B途径的p65所必需的。在这里，我们报告的CT 441作为一个尾巴特异性蛋白酶的特性。CT 441含有蛋白质-蛋白质相互作用的PDZ结构域和Ser/Lys二联体催化单元。Ser 455或Lys 481突变。在活性位点中，消除了CT 441对p65切割的活性。此外，我们发现在感染的中期和晚期检测到的CT 441 Tsp的产生与p65切割活性相关。除了高度同源性，人和小鼠p65蛋白还含有相同的22个氨基酸（aa）残基的C-末端尾。然而，只有人p65对切割敏感。利用分子生物学方法，我们将p65切割位点定位到与小鼠p65不同的6个氨基酸残基的区域。此外，用脯氨酸取代T352抑制p65切割。总之，该研究表明，CT 441是一种尾部特异性蛋白酶，能够干扰宿主抗菌和炎症反应的NF-κ B途径。
Chlamydia species are bacterial pathogens that affect over 140 million individuals worldwide. Ocular infection by Chlamydia trachomatis is the leading cause of preventable blindness, and urogenital tract infection by Chlamydia causes sexually transmitted disease. As obligate intracellular organisms, Chlamydia species have evolved mechanisms to evade the host immune system, including the degradation of the transcription factors regulatory factor X5 and upstream stimulation factor 1, which are required for the expression of major histocompatibility complex molecules I and II by CPAF and cleavage of p65 of the NF-kappa B pathway by the encoded CT441 protein. Here, we report the characterization of CT441 as a tail-specific protease. CT441 contains a PDZ domain of protein-protein interactions and a Ser/Lys dyad catalytic unit. Mutation at either Ser455 or Lys481. in the active site ablated CT441 activity of p65 cleavage. In addition, we found that the production of CT441 Tsp, which was detected at the middle and late stages of an infection, correlated with p65 cleavage activity. In addition to high homology, human and mouse p65 proteins also contain an identical C-terminal tail of 22 amino acid (aa) residues. However, only human p65 was susceptible to cleavage. Using molecular biology approaches, we mapped the p65 cleavage site(s) to a region that differs from that of mouse p65 by 6 aa residues. Additionally, the substitution of T352 with a proline inhibited p65 cleavage. Together, the study demonstrates that CT441 is a tail-specific protease that is capable of interfering with the NF-kappa B pathway of host antimicrobial and inflammatory responses.