Regulators of the proteasome pathway, Uch37 and Rpn13, play distinct roles in mouse development.
Regulators of the proteasome pathway, Uch37 and Rpn13, play distinct roles in mouse development.
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DOI：
10.1371/journal.pone.0013654
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发表时间：
2010-10-27
期刊：
影响因子：
3.7
通讯作者：
Oravecz T
中科院分区：
文献类型：
--
作者：
Al-Shami A;Jhaver KG;Vogel P;Wilkins C;Humphries J;Davis JJ;Xu N;Potter DG;Gerhardt B;Mullinax R;Shirley CR;Anderson SJ;Oravecz T
rpn 13是一种新的哺乳动物蛋白酶体受体，最近被确定为卵巢癌的扩增靶点。它可以与泛素相互作用并激活26 S蛋白酶体上的去泛素化酶Uch 37。由于Rpn 13和Uch 37都不是一个完整的蛋白酶体亚基，我们探讨了这两种蛋白质是否对哺乳动物的发育和生存至关重要。Uch 37的缺失导致与胚胎脑发育严重缺陷相关的小鼠产前致死。相比之下，大多数Rpn 13缺陷小鼠存活至成年，尽管它们出生时较小，数量少于野生型同窝仔。Rpn 13的缺乏对蛋白酶体功能产生组织特异性影响：肾上腺和淋巴器官中的蛋白酶体活性增加，睾丸和大脑中的活性降低。成年Rpn 13 −/−小鼠达到正常体重，但体内脂肪含量增加，并且由于配子发生缺陷而不育。此外，Rpn 13 −/−小鼠显示T细胞数量增加，类似于生长激素介导的效应。事实上，Rpn 13 −/−小鼠的血清生长激素和促卵泡激素水平显著增加，而睾丸中的生长激素受体表达减少。总之，这是第一份报告，其特征的生理作用Uch 37和Rpn 13在小鼠的发展和牵连的非ATP酶蛋白酶体蛋白，Rpn 13，在配子发生的过程中。
Rpn13 is a novel mammalian proteasomal receptor that has recently been identified as an amplification target in ovarian cancer. It can interact with ubiquitin and activate the deubiquitinating enzyme Uch37 at the 26S proteasome. Since neither Rpn13 nor Uch37 is an integral proteasomal subunit, we explored whether either protein is essential for mammalian development and survival. Deletion of Uch37 resulted in prenatal lethality in mice associated with severe defect in embryonic brain development. In contrast, the majority of Rpn13-deficient mice survived to adulthood, although they were smaller at birth and fewer in number than wild-type littermates. Absence of Rpn13 produced tissue-specific effects on proteasomal function: increased proteasome activity in adrenal gland and lymphoid organs, and decreased activity in testes and brain. Adult Rpn13−/− mice reached normal body weight but had increased body fat content and were infertile due to defective gametogenesis. Additionally, Rpn13−/− mice showed increased T-cell numbers, resembling growth hormone-mediated effects. Indeed, serum growth hormone and follicular stimulating hormone levels were significantly increased in Rpn13−/− mice, while growth hormone receptor expression was reduced in the testes. In conclusion, this is the first report characterizing the physiological roles of Uch37 and Rpn13 in murine development and implicating a non-ATPase proteasomal protein, Rpn13, in the process of gametogenesis.
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