TMED2 binding restricts SMO to the ER and Golgi compartments.
TMED2 binding restricts SMO to the ER and Golgi compartments.
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DOI：
10.1371/journal.pbio.3001596
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发表时间：
2022-03
期刊：
影响因子：
9.8
通讯作者：
中科院分区：
文献类型：
--
作者：
刺猬（HH）信号对于胚胎模式和干细胞分化很重要。 OID逃脱了我们确定高尔基蛋白TMED2和TMED10是SMO调节的因素。我们证明了这一点中性分化中的相互作用，其中TMed2功能抑制HH信号强度。
刺猬通过结合受体修补并限制信号换能器平稳的遗传筛选来表明组织的组织模式。
Hedgehog (HH) signaling is important for embryonic pattering and stem cell differentiation. The G protein–coupled receptor (GPCR) Smoothened (SMO) is the key HH signal transducer modulating both transcription-dependent and transcription-independent responses. We show that SMO protects naive mouse embryonic stem cells (ESCs) from dissociation-induced cell death. We exploited this SMO dependency to perform a genetic screen in haploid ESCs where we identify the Golgi proteins TMED2 and TMED10 as factors for SMO regulation. Super-resolution microscopy shows that SMO is normally retained in the endoplasmic reticulum (ER) and Golgi compartments, and we demonstrate that TMED2 binds to SMO, preventing localization to the plasma membrane. Mutation of TMED2 allows SMO accumulation at the plasma membrane, recapitulating early events after HH stimulation. We demonstrate the physiologic relevance of this interaction in neural differentiation, where TMED2 functions to repress HH signal strength. Identification of TMED2 as a binder and upstream regulator of SMO opens the way for unraveling the events in the ER–Golgi leading to HH signaling activation. Hedgehog signals orchestrate tissue patterning by binding the receptor Patched and restricting the signal transducer Smoothened. A genetic screen reveals Tmed2 as a new interactor of Smoothened that is required for regulating Smoothened transport from the endoplasmic reticulum and Golgi to the plasma membrane and hence modulating the strength of Hedgehog signal transduction.
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