Koseki T, Inohara N, Chen S, Carrio R, Merino J, Hottiger M O, Nabel G J, Núñez G
Department of Pathology and Comprehensive Cancer Center, The University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
J Biol Chem. 1999 Apr 9;274(15):9955-61. doi: 10.1074/jbc.274.15.9955.
We have identified and characterized CIPER, a novel protein containing a caspase recruitment domain (CARD) in its N terminus and a C-terminal region rich in serine and threonine residues. The CARD of CIPER showed striking similarity to E10, a product of the equine herpesvirus-2. CIPER formed homodimers via its CARD and interacted with viral E10 but not with several apoptosis regulators containing CARDs including ARC, RAIDD, RICK, caspase-2, caspase-9, or Apaf-1. Expression of CIPER induced NF-kappaB activation, which was inhibited by dominant-negative NIK and a nonphosphorylable IkappaB-alpha mutant but not by dominant-negative RIP. Mutational analysis revealed that the N-terminal region of CIPER containing the CARD was sufficient and necessary for NF-kappaB-inducing activity. Point mutations in highly conserved residues in the CARD of CIPER disrupted the ability of CIPER to activate NF-kappaB and to form homodimers, indicating that the CARD is essential for NF-kappaB activation and dimerization. We propose that CIPER acts in a NIK-dependent pathway of NF-kappaB activation.
我们已经鉴定并表征了CIPER，这是一种新型蛋白质，其N端含有一个半胱天冬酶募集结构域（CARD），C端富含丝氨酸和苏氨酸残基。CIPER的CARD与马疱疹病毒2的产物E10有显著相似性。CIPER通过其CARD形成同源二聚体，并与病毒E10相互作用，但不与包括ARC、RAIDD、RICK、半胱天冬酶-2、半胱天冬酶-9或凋亡蛋白酶激活因子-1在内的几种含有CARD的凋亡调节因子相互作用。CIPER的表达诱导了核因子κB（NF-κB）的激活，显性负性NIK和不可磷酸化的κBα突变体可抑制这种激活，但显性负性RIP则不能。突变分析表明，CIPER含有CARD的N端区域对于诱导NF-κB的活性是充分且必要的。CIPER的CARD中高度保守残基的点突变破坏了CIPER激活NF-κB和形成同源二聚体的能力，表明CARD对于NF-κB的激活和二聚化至关重要。我们提出CIPER在NF-κB激活的NIK依赖性途径中发挥作用。
