FNDC5/irisin facilitates muscle-adipose-bone connectivity through ubiquitination-dependent activation of runt-related transcriptional factors RUNX1/2.
FNDC5/irisin facilitates muscle-adipose-bone connectivity through ubiquitination-dependent activation of runt-related transcriptional factors RUNX1/2.
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FNDC5/irisin 通过泛素化依赖性激活 runt 相关转录因子 RUNX1/2 来促进肌肉-脂肪-骨骼的连接。
DOI：
10.1016/j.jbc.2022.101679
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发表时间：
2022-03
期刊：
影响因子：
--
通讯作者：
Gan X
中科院分区：
文献类型：
--
作者：
He X;Hua Y;Li Q;Zhu W;Pan Y;Yang Y;Li X;Wu M;Wang J;Gan X
在过去的十年中，运动刺激骨骼肌中的纤维连接蛋白III型结构域含蛋白5(FNDC5)产生的切割蛋白Irisin日益成为与人类代谢综合征和骨质疏松症相关的生物标志物。然而，目前还不清楚该蛋白如何在代谢和骨骼动态平衡中促进肌肉−脂肪−的骨连接。在本研究中，我们意外地观察到FNDC5基因在棕色脂肪细胞分化过程中可以显著激活，而在白色脂肪细胞分化过程中不能激活，并且FNDC5在小鼠棕色脂肪组织(BAT)中特异表达。但与骨骼肌不同的是，蝙蝠体内FNDC5/Irisin的表达是通过寒冷暴露而不是运动促进的。启动子活性和染色质免疫沉淀分析进一步表明，过氧化体增殖物激活受体γ辅活化子-1α和甲状腺激素受体共同作用于FNDC5基因启动子，诱导其转录。我们发现，在骨骼和皮下白色脂肪组织中，FNDC5/Irisin通过粘着斑激酶依赖的途径刺激矮小相关转录因子RUNX1/2。机制上，粘着斑激酶被FNDC5/Irisin激活，然后促进E3泛素蛋白连接酶WW结构域蛋白2泛素化，随后激活RUNX1/2，最终激活成骨细胞相关或产热相关基因。有趣的是，含有PR结构域的蛋白16对皮下白色脂肪的“褐化”和骨骼发育至关重要，它被发现以一种依赖于WW结构域的蛋白2的方式与RUNX1/2形成复合体。这些发现阐明了FNDC5/Irisin支持肌肉−脂肪−骨连接，特别是蝙蝠−骨连接的信号机制。
In the past decade, the cleavage protein irisin derived from fibronectin type III domain–containing protein 5 (FNDC5) in exercise-stimulated skeletal muscle has increasingly become a biomarker associated with metabolic syndrome and osteoporosis in humans. However, it is unclear how this protein facilitates muscle−adipose−bone connectivity in metabolic and skeletal homeostasis. In this study, we unexpectedly observed that the FNDC5 gene can be markedly activated during the differentiation of brown adipocytes but not white adipocytes, and that FNDC5 is specifically expressed in mouse brown adipose tissues (BATs). But unlike it in the skeletal muscles, the expression of FNDC5/irisin in BAT is promoted by cold exposure rather than exercise in mice. Analysis of promoter activity and chromatin immunoprecipitation further showed that peroxisome proliferator–activated receptor γ coactivator-1α and thyroid hormone receptors cooperate on the FNDC5 gene promoter to induce its transcription. We found that FNDC5/irisin stimulates the runt-related transcriptional factors RUNX1/2 via a focal adhesion kinase–dependent pathway in both bone and subcutaneous white adipose tissues. Mechanistically, focal adhesion kinase is stimulated by FNDC5/irisin and then facilitates E3 ubiquitin–protein ligase WW domain–containing protein 2 to ubiquitinate and subsequently activate RUNX1/2, culminating in the activation of osteoblast-related or thermogenesis-related genes. Interestingly, the PR domain containing protein 16 that is crucial for subcutaneous white adipose “browning” and skeletal development was found to form a complex with RUNX1/2 in a WW domain–containing protein 2-dependent manner. These findings elucidate a signaling mechanism by which FNDC5/irisin supports the muscle−adipose−bone connectivity, especially BAT−bone connectivity.
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DOI：
10.1007/s00198-012-2110-y
发表时间：
2013-04
期刊：
Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA
影响因子：
--
作者：
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