The ubiquitination status of the glucagon receptor determines signal bias.
The ubiquitination status of the glucagon receptor determines signal bias.
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DOI：
10.1016/j.jbc.2023.104690
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发表时间：
2023-05
影响因子：
4.8
通讯作者：
Shenoy, Sudha K.
中科院分区：
文献类型：
--
作者：
Kaur, Suneet;Sokrat, Badr;Capozzi, Megan E.;El, Kimberley;Bai, Yushi;Jazic, Aeva;Han, Bridgette;Kumar, Kaavya Krishna;D'Alessio, David A.;Campbell, Jonathan E.;Bouvier, Michel;Shenoy, Sudha K.
胰腺激素胰高血糖素激活胰高血糖素受体（GCGR），这是一种B类七跨膜G蛋白偶联受体，与刺激性异源三聚体G蛋白偶联，并引发对肝脏葡萄糖代谢和胰岛胰岛素分泌至关重要的PKA依赖性信号级联。胰高血糖素刺激还启动内吞衔接子β arrestin 1和β arrestin 2的募集，其调节GCGR的脱敏和内化。与许多其他G蛋白偶联受体不同，在质膜上表达的GCGR是组成性泛素化的，并且在激动剂活化后，内化的GCGR在早期内体去泛素化并通过含有Rab 4的囊泡再循环。在这里，我们报告了一个新的泛素化状态和GCGR的信号转导机制之间的联系。在去泛素化状态下，GCGR与Gs的偶联减少，而与β抑制蛋白的结合增强，信号传导偏向于β抑制蛋白1依赖性p38丝裂原活化蛋白激酶（MAPK）途径。这种泛素依赖性信号传导偏差是通过跨膜螺旋V的细胞质表面上的赖氨酸333（K333）的修饰而产生的。与GCGR-WT相比，突变体GCGR-K333 R具有受损的泛素化、减少的G蛋白偶联和PKA信号传导，但未受损的葡萄糖刺激的胰岛素分泌对激动剂刺激的增强作用，这涉及p38 MAPK信号传导。WT和GCGR-K333 R均促进胰高血糖素诱导的β抑制蛋白1依赖性p38信号传导支架的形成，该支架需要典型的上游MAPK-激酶3，但不依赖于Gs、Gi和β抑制蛋白2。因此，GCGR中K333处的泛素化/去泛素化定义了不同换能器的激活，其具有影响健康和疾病中胰高血糖素信号传导的各个方面的潜力。
The pancreatic hormone glucagon activates the glucagon receptor (GCGR), a class B seven-transmembrane G protein-coupled receptor that couples to the stimulatory heterotrimeric G protein and provokes PKA-dependent signaling cascades vital to hepatic glucose metabolism and islet insulin secretion. Glucagon-stimulation also initiates recruitment of the endocytic adaptors, βarrestin1 and βarrestin2, which regulate desensitization and internalization of the GCGR. Unlike many other G protein-coupled receptors, the GCGR expressed at the plasma membrane is constitutively ubiquitinated and upon agonist-activation, internalized GCGRs are deubiquitinated at early endosomes and recycled via Rab4-containing vesicles. Herein we report a novel link between the ubiquitination status and signal transduction mechanism of the GCGR. In the deubiquitinated state, coupling of the GCGR to Gs is diminished, while binding to βarrestin is enhanced with signaling biased to a βarrestin1–dependent p38 mitogen activated protein kinase (MAPK) pathway. This ubiquitin-dependent signaling bias arises through the modification of lysine333 (K333) on the cytoplasmic face of transmembrane helix V. Compared with the GCGR-WT, the mutant GCGR-K333R has impaired ubiquitination, diminished G protein coupling, and PKA signaling but unimpaired potentiation of glucose-stimulated–insulin secretion in response to agonist-stimulation, which involves p38 MAPK signaling. Both WT and GCGR-K333R promote the formation of glucagon-induced βarrestin1–dependent p38 signaling scaffold that requires canonical upstream MAPK-Kinase3, but is independent of Gs, Gi, and βarrestin2. Thus, ubiquitination/deubiquitination at K333 in the GCGR defines the activation of distinct transducers with the potential to influence various facets of glucagon signaling in health and disease.
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影响因子：
56.9
作者：
Ge, BX;Gram, H;Han, JH
通讯作者：
Han, JH
DOI：
10.1083/jcb.201504007
发表时间：
2015-09-28
期刊：
The Journal of cell biology
影响因子：
--
作者：
Grimsey NJ;Aguilar B;Smith TH;Le P;Soohoo AL;Puthenveedu MA;Nizet V;Trejo J
通讯作者：
Trejo J
影响因子：
4.8
作者：
Cao, WH;Collins, QF;Collins, S
通讯作者：
Collins, S
DOI：
10.1111/tra.12619
发表时间：
2019-03
期刊：
Traffic (Copenhagen, Denmark)
影响因子：
--
作者：
Dores MR;Trejo J
通讯作者：
Trejo J
影响因子：
8.8
作者：
Ghosh, Eshan;Dwivedi, Hemlata;Shukla, Arun K.
通讯作者：
Shukla, Arun K.