Cai Tao, Fukushige Tetsunari, Notkins Abner L, Krause Michael
Experimental Medicine Section, Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892, USA.
J Neurosci. 2004 Mar 24;24(12):3115-24. doi: 10.1523/JNEUROSCI.0101-04.2004.
IA-2 (insulinoma-associated protein 2), a major autoantigen in type 1 diabetes, is a receptor-tyrosine phosphatase-like protein associated with the membrane of secretory granules of neural and endocrine-specific cells. Loss of IA-2 activity in the mouse results in reduced insulin release and additional phenotypes, consistent with a general effect on neurosecretion and hormone release. To gain further insight into the cellular mechanisms of IA-2 function, we have studied the Caenorhabditis elegans homolog, CeIA-2 encoded by the ida-1 gene. Using two independent putative null alleles of ida-1, we demonstrate that animals lacking CeIA-2 activity are viable and exhibit subtle defects. Genetic studies of mutants in ida-1 and several genes involved in neurosecretory vesicle cargo release and signaling highlight two roles for CeIA-2. First, CeIA-2 has a specific and novel genetic interaction with UNC-31/CAPS, a protein that has been shown in other systems to regulate dense-core vesicle cargo release. Second, loss of CeIA-2 activity enhances weak alleles in the insulin-like signaling pathway. These results suggest that CeIA-2 may be an important factor in dense-core vesicle cargo release with parallels to insulin signaling in mammals.
IA-2（胰岛素瘤相关蛋白2）是1型糖尿病中的一种主要自身抗原，是一种与神经和内分泌特异性细胞分泌颗粒膜相关的受体酪氨酸磷酸酶样蛋白。小鼠中IA-2活性的丧失导致胰岛素释放减少及其他表型，这与对神经分泌和激素释放的普遍影响一致。为了进一步深入了解IA-2功能的细胞机制，我们研究了秀丽隐杆线虫的同源物，即由ida-1基因编码的CeIA-2。利用ida-1的两个独立的假定无效等位基因，我们证明缺乏CeIA-2活性的动物是有活力的，并且表现出细微的缺陷。对ida-1及几个参与神经分泌囊泡货物释放和信号传导的基因的突变体进行的遗传学研究突出了CeIA-2的两个作用。首先，CeIA-2与UNC-31/CAPS存在特定的新型遗传相互作用，UNC-31/CAPS是一种在其他系统中已被证明可调节致密核心囊泡货物释放的蛋白质。其次，CeIA-2活性的丧失增强了胰岛素样信号通路中的弱等位基因。这些结果表明，CeIA-2可能是致密核心囊泡货物释放中的一个重要因素，与哺乳动物中的胰岛素信号传导有相似之处。
