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突触后 ErbB4 的胞转和跨突触保留是 NRG3 在轴突中积累的基础。

Transcytosis and trans-synaptic retention by postsynaptic ErbB4 underlie axonal accumulation of NRG3.

机构信息

Section on Molecular Neurobiology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD.

Multidisciplinary Centre for Advanced Research and Studies, Jamia Millia Islamia, New Delhi, India.

出版信息

J Cell Biol. 2022 Jul 4;221(7). doi: 10.1083/jcb.202110167. Epub 2022 May 17.

DOI:10.1083/jcb.202110167
PMID:35579602
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9118086/
Abstract

Neuregulins (NRGs) are EGF-like ligands associated with cognitive disorders. Unprocessed proNRG3 is cleaved by BACE1 to generate the mature membrane-bound NRG3 ligand, but the subcellular site of proNRG3 cleavage, mechanisms underlying its transport into axons, and presynaptic accumulation remain unknown. Using an optogenetic proNRG3 cleavage reporter (LA143-NRG3), we investigate the spatial-temporal dynamics of NRG3 processing and sorting in neurons. In dark conditions, unprocessed LA143-NRG3 is retained in the trans-Golgi network but, upon photoactivation, is cleaved by BACE1 and released from the TGN. Mature NRG3 then emerges on the somatodendritic plasma membrane from where it is re-endocytosed and anterogradely transported on Rab4+ vesicles into axons via transcytosis. By contrast, the BACE1 substrate APP is sorted into axons on Rab11+ vesicles. Lastly, by a mechanism we denote "trans-synaptic retention," NRG3 accumulates at presynaptic terminals by stable interaction with its receptor ErbB4 on postsynaptic GABAergic interneurons. We propose that trans-synaptic retention may account for polarized expression of other neuronal transmembrane ligands and receptors.

摘要

神经调节蛋白（NRGs）是与认知障碍相关的 EGF 样配体。未加工的前 NRG3 被 BACE1 切割生成成熟的膜结合 NRG3 配体，但前 NRG3 切割的亚细胞部位、其向轴突转运的机制以及前突触积累仍然未知。使用光遗传的 proNRG3 切割报告基因（LA143-NRG3），我们研究了神经元中 NRG3 加工和分拣的时空动态。在黑暗条件下，未加工的 LA143-NRG3 保留在反式高尔基网络中，但在光激活后，被 BACE1 切割并从 TGN 释放。成熟的 NRG3 随后出现在体树突质膜上，从那里它被重新内吞，并通过跨细胞运输在 Rab4+ 囊泡中逆行转运到轴突中。相比之下，BACE1 底物 APP 被分拣到 Rab11+ 囊泡中的轴突中。最后，通过我们称为“跨突触保留”的机制，NRG3 通过与突触后 GABA 能中间神经元上的受体 ErbB4 的稳定相互作用，在前突触末端积累。我们提出，跨突触保留可能解释了其他神经元跨膜配体和受体的极化表达。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3ce0/9118086/3b01d77c4988/JCB_202110167_Fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3ce0/9118086/9071f07fbd2d/JCB_202110167_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3ce0/9118086/ddfd040f1005/JCB_202110167_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3ce0/9118086/4a042355fd8a/JCB_202110167_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3ce0/9118086/c6f960c134db/JCB_202110167_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3ce0/9118086/76a42193dbb7/JCB_202110167_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3ce0/9118086/d87de6286868/JCB_202110167_FigS4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3ce0/9118086/3c08d191e104/JCB_202110167_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3ce0/9118086/81ebfcbaa9a5/JCB_202110167_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3ce0/9118086/613b2f6c1df4/JCB_202110167_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3ce0/9118086/ba2a94d596c4/JCB_202110167_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3ce0/9118086/f5036adf9f58/JCB_202110167_FigS5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3ce0/9118086/84eb53cf3001/JCB_202110167_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3ce0/9118086/3b01d77c4988/JCB_202110167_Fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3ce0/9118086/9071f07fbd2d/JCB_202110167_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3ce0/9118086/ddfd040f1005/JCB_202110167_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3ce0/9118086/4a042355fd8a/JCB_202110167_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3ce0/9118086/c6f960c134db/JCB_202110167_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3ce0/9118086/76a42193dbb7/JCB_202110167_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3ce0/9118086/d87de6286868/JCB_202110167_FigS4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3ce0/9118086/3c08d191e104/JCB_202110167_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3ce0/9118086/81ebfcbaa9a5/JCB_202110167_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3ce0/9118086/613b2f6c1df4/JCB_202110167_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3ce0/9118086/ba2a94d596c4/JCB_202110167_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3ce0/9118086/f5036adf9f58/JCB_202110167_FigS5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3ce0/9118086/84eb53cf3001/JCB_202110167_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3ce0/9118086/3b01d77c4988/JCB_202110167_Fig8.jpg

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