Integral Membrane Protein 2A Is a Negative Regulator of Canonical and Non-Canonical Hedgehog Signalling.
Integral Membrane Protein 2A Is a Negative Regulator of Canonical and Non-Canonical Hedgehog Signalling.
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整体膜蛋白2a是规范和非刺猬信号传导的负调节剂。
DOI：
10.3390/cells10082003
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发表时间：
2021-08-06
期刊：
影响因子：
6
通讯作者：
Riobo-Del Galdo NA
中科院分区：
文献类型：
--
作者：
Morales-Alcala CC;Georgiou IC;Timmis AJ;Riobo-Del Galdo NA
Hedgehog（Hh）受体PTCH 1和整合膜蛋白2A（ITM 2A）通过减少自溶体形成来抑制自噬。在这项研究中，我们证明了ITM 2A与PTCH 1的物理相互作用;然而，这两种蛋白质独立地抑制自噬通量，因为ITM 2A的沉默并不能阻止LC 3BII和p62在PTCH 1过表达细胞中的积累，这表明它们提供了限制自噬的替代模式。ITM 2A的敲低增强PTCH 1诱导的自噬通量阻断并增加PTCH 1表达，而ITM 2A过表达降低PTCH 1蛋白水平，表明它是PTCH 1非经典信号传导的负调节剂。我们的研究还表明，内源性ITM 2A是必要的及时诱导肌分化标志物在C2 C12细胞，因为部分敲低延迟分化的时间。我们还发现，在肌源性分化期间，基础自噬通量减少，同时ITM 2A表达增加。鉴于经典Hh信号传导阻止肌源性分化，我们使用GLI-荧光素酶测定研究了ITM 2A对经典Hh信号传导的影响。我们的研究结果表明，ITM 2A是GLI转录活性和GLI 1稳定性的强负调节因子。总之，ITM 2A负调节经典和非经典Hh信号传导。
The Hedgehog (Hh) receptor PTCH1 and the integral membrane protein 2A (ITM2A) inhibit autophagy by reducing autolysosome formation. In this study, we demonstrate that ITM2A physically interacts with PTCH1; however, the two proteins inhibit autophagic flux independently, since silencing of ITM2A did not prevent the accumulation of LC3BII and p62 in PTCH1-overexpressing cells, suggesting that they provide alternative modes to limit autophagy. Knockdown of ITM2A potentiated PTCH1-induced autophagic flux blockade and increased PTCH1 expression, while ITM2A overexpression reduced PTCH1 protein levels, indicating that it is a negative regulator of PTCH1 non-canonical signalling. Our study also revealed that endogenous ITM2A is necessary for timely induction of myogenic differentiation markers in C2C12 cells since partial knockdown delays the timing of differentiation. We also found that basal autophagic flux decreases during myogenic differentiation at the same time that ITM2A expression increases. Given that canonical Hh signalling prevents myogenic differentiation, we investigated the effect of ITM2A on canonical Hh signalling using GLI-luciferase assays. Our findings demonstrate that ITM2A is a strong negative regulator of GLI transcriptional activity and of GLI1 stability. In summary, ITM2A negatively regulates canonical and non-canonical Hh signalling.
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影响因子：
4.5
作者：
Mellis D;Staines KA;Peluso S;Georgiou IC;Dora N;Kubiak M;Van't Hof R;Grillo M;Farquharson C;Kinsella E;Thornburn A;Ralston SH;Salter DM;Riobo-Del Galdo NA;Hill RE;Ditzel M
通讯作者：
Ditzel M
DOI：
10.1073/pnas.1200094109
发表时间：
2012-06-26
影响因子：
11.1
作者：
Fombonne, Joanna;Bissey, Pierre-Antoine;Mehlen, Patrick
通讯作者：
Mehlen, Patrick
影响因子：
3.9
作者：
Mitsui, Shinichi;Osako, Yoji;Yuri, Kazunari
通讯作者：
Yuri, Kazunari
DOI：
10.1084/jem.190.2.217
发表时间：
1999-07-19
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Kirchner J;Bevan MJ
通讯作者：
Bevan MJ
影响因子：
5.3
作者：
Chen, Xiaole L.;Chinchilla, Pilar;Riobo, Natalia A.
通讯作者：
Riobo, Natalia A.