The UBR-1 ubiquitin ligase regulates glutamate metabolism to generate coordinated motor pattern in Caenorhabditis elegans.
The UBR-1 ubiquitin ligase regulates glutamate metabolism to generate coordinated motor pattern in Caenorhabditis elegans.
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DOI：
10.1371/journal.pgen.1007303
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发表时间：
2018-04
期刊：
影响因子：
4.5
通讯作者：
Zhen M
中科院分区：
文献类型：
--
作者：
Chitturi J;Hung W;Rahman AMA;Wu M;Lim MA;Calarco J;Baran R;Huang X;Dennis JW;Zhen M
UBR 1是一种E3泛素连接酶，以其通过N端规则靶向蛋白质降解的能力而闻名。然而，UBR家族蛋白的生理功能仍不完全清楚。我们发现C. elegans UBR-1导致特定的运动缺陷：当成年动物产生反向运动时，A类运动神经元表现出同步激活，阻止身体弯曲。这种运动缺陷是通过去除GOT-1来挽救的，GOT-1是一种将天冬氨酸转化为谷氨酸的转氨酶。UBR-1和GOT-1都在反向运动回路的前运动中间神经元中表达，并且是调节运动模式所必需的。UBR-1和GOT-1突变体分别表现出升高和降低的谷氨酸水平。这些结果提出了一个有趣的可能性，即UBR蛋白调节谷氨酸代谢，这对神经元发育和信号传导至关重要。泛素介导的蛋白质降解是多种生物过程的核心。降解底物的选择是由E3泛素连接酶进行的，它靶向特定的蛋白质组进行泛素化。人类基因组编码数百种E3连接酶;许多在动物物种中表现出序列保守性，包括一种称为UBR 1的连接酶。携带UBR 1突变的患者表现出严重的系统性缺陷，但UBR 1生理功能背后的生物学仍然难以捉摸。我们发现C.线虫UBR-1调节谷氨酸水平。当UBR-1有缺陷时，C.线虫表现出增加的谷氨酸;这导致运动神经元活动的同步，因此当动物到达成年时，运动缺陷。UBR 1介导的谷氨酸代谢可能导致UBR 1突变的生理缺陷。
UBR1 is an E3 ubiquitin ligase best known for its ability to target protein degradation by the N-end rule. The physiological functions of UBR family proteins, however, remain not fully understood. We found that the functional loss of C. elegans UBR-1 leads to a specific motor deficit: when adult animals generate reversal movements, A-class motor neurons exhibit synchronized activation, preventing body bending. This motor deficit is rescued by removing GOT-1, a transaminase that converts aspartate to glutamate. Both UBR-1 and GOT-1 are expressed and critically required in premotor interneurons of the reversal motor circuit to regulate the motor pattern. ubr-1 and got-1 mutants exhibit elevated and decreased glutamate level, respectively. These results raise an intriguing possibility that UBR proteins regulate glutamate metabolism, which is critical for neuronal development and signaling. Ubiquitin-mediated protein degradation is central to diverse biological processes. The selection of substrates for degradation is carried out by the E3 ubiquitin ligases, which target specific groups of proteins for ubiquitination. The human genome encodes hundreds of E3 ligases; many exhibit sequence conservation across animal species, including one such ligase called UBR1. Patients carrying mutations in UBR1 exhibit severe systemic defects, but the biology behinds UBR1’s physiological function remains elusive. Here we found that the C. elegans UBR-1 regulates glutamate level. When UBR-1 is defective, C. elegans exhibits increased glutamate; this leads to synchronization of motor neuron activity, hence defective locomotion when animals reach adulthood. UBR1-mediated glutamate metabolism may contribute to the physiological defects of UBR1 mutations.
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影响因子：
7.1
作者：
Hawkins, Richard A.
通讯作者：
Hawkins, Richard A.
影响因子：
3
作者：
Ben Arous, Juliette;Tanizawa, Yoshinori;Schafer, William R.
通讯作者：
Schafer, William R.
影响因子：
3.7
作者：
Faumont S;Rondeau G;Thiele TR;Lawton KJ;McCormick KE;Sottile M;Griesbeck O;Heckscher ES;Roberts WM;Doe CQ;Lockery SR
通讯作者：
Lockery SR
影响因子：
3.7
作者：
Doitsidou M;Poole RJ;Sarin S;Bigelow H;Hobert O
通讯作者：
Hobert O
DOI：
10.1073/pnas.0409009101
发表时间：
2005-03-01
影响因子：
11.1
作者：
Gray, JM;Hill, JJ;Bargmann, CI
通讯作者：
Bargmann, CI