Abnormal regulation of TSG101 in mice with spongiform neurodegeneration.
Abnormal regulation of TSG101 in mice with spongiform neurodegeneration.
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DOI：
10.1016/j.bbadis.2009.08.009
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发表时间：
2009-10
影响因子：
6.2
通讯作者：
Gunn, Teresa M.
中科院分区：
文献类型：
--
作者：
Jiao, Jian;Sun, Kaihua;Walker, Will P.;Bagher, Pooneh;Cota, Christina D.;Gunn, Teresa M.
关键词：
海绵状神经变性的特点是整个中枢神经系统出现空泡。它有许多潜在的原因，但潜在的细胞机制尚不清楚。缺乏E3泛素连接酶Mahogunin Ring Finger-1 （MGRN1）的小鼠会发生年龄依赖性海绵状脑病。我们发现MGRN1中的“PSAP”基序与TSG101的泛素E2变体（UEV）结构域之间存在相互作用，TSG101是运输I所需的内体分选复合物（ESCRT-I）的一个组成部分，并证明MGRN1多单泛素化TSG101。我们研究了MGRN1缺失对小鼠大脑中TSG101表达和功能的体内影响。TSG101泛素化模式在野生型小鼠和Mgrn1零突变小鼠的大脑中有所不同：1月龄时，零突变小鼠的TSG101泛素化程度较低，而在成年时，突变小鼠的TSG101泛素化程度高于野生型小鼠。在突变的大脑中，表皮生长因子受体（EGFR）水平增加。这些结果表明，MGRN1的缺失促进了TSG101被其他E3s泛素化，并可能阻止其与内体膜分离或导致其形成不溶性聚集体。我们的数据表明，在Mgrn1零突变小鼠海绵状神经退行性变的发病机制中，TSG101在内切溶酶体运输中的正常功能缺失。
Spongiform neurodegeneration is characterized by the appearance of vacuoles throughout the central nervous system. It has many potential causes, but the underlying cellular mechanisms are not well understood. Mice lacking the E3 ubiquitin ligase Mahogunin Ring Finger-1 (MGRN1) develop age-dependent spongiform encephalopathy. We identified an interaction between a “PSAP” motif in MGRN1 and the ubiquitin E2 variant (UEV) domain of TSG101, a component of the endosomal sorting complex required for transport I (ESCRT-I), and demonstrate that MGRN1 multimonoubiquitinates TSG101. We examined the in vivo consequences of loss of MGRN1 on TSG101 expression and function in the mouse brain. The pattern of TSG101 ubiquitination differed in the brains of wild-type mice and Mgrn1 null mutant mice: at 1 month of age, null mutant mice had less ubiquitinated TSG101, while in adults, mutant mice had more ubiquitinated, insoluble TSG101 than wild-type mice. There was an associated increase in epidermal growth factor receptor (EGFR) levels in mutant brains. These results suggest that loss of MGRN1 promotes ubiquitination of TSG101 by other E3s and may prevent its disassociation from endosomal membranes or cause it to form insoluble aggregates. Our data implicate loss of normal TSG101 function in endo-lysosomal trafficking in the pathogenesis of spongiform neurodegeneration in Mgrn1 null mutant mice.
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