Transcytosis and trans-synaptic retention by postsynaptic ErbB4 underlie axonal accumulation of NRG3.
Transcytosis and trans-synaptic retention by postsynaptic ErbB4 underlie axonal accumulation of NRG3.
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DOI：
10.1083/jcb.202110167
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发表时间：
2022-07-04
影响因子：
7.8
通讯作者：
Buonanno, Andres
中科院分区：
文献类型：
--
作者：
Ahmad, Tanveer;Vullhorst, Detlef;Chaudhuri, Rituparna;Guardia, Carlos M.;Chaudhary, Nisha;Karavanova, Irina;Bonifacino, Juan S.;Buonanno, Andres
Ahmad及其同事报道，NRG3的突触前积累涉及多个过程，包括在BACE1切割后TGN释放含有egf的结构域，从体树突到轴突质膜的胞质作用，以及通过与突触后ErbB4受体的突触间相互作用在谷氨酸末端的选择性保留。神经调节蛋白（NRGs）是与认知障碍相关的egf样配体。未加工的proNRG3被BACE1切割以产生成熟的膜结合NRG3配体，但proNRG3切割的亚细胞位点、其转运到轴突的机制以及突触前积累尚不清楚。利用光遗传学proNRG3切割报告基因LA143-NRG3，研究了NRG3在神经元中加工和分选的时空动态。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中释放出来。成熟的NRG3随后出现在体树突质膜上，在那里它被再内吞，并通过胞吞作用在Rab4+囊泡上顺行运输到轴突。相比之下，BACE1底物APP在Rab11+囊泡上被分类为轴突。最后，通过一种我们称为“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的稳定相互作用在突触前末端积累。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。
Ahmad and colleagues report that presynaptic accumulation of NRG3 involves multiple processes that include release of the EGF-containing domain from the TGN following BACE1 cleavage, transcytosis from somatodendritic to axonal plasma membranes, and selective retention at glutamatergic terminals through trans-synaptic interactions with postsynaptic ErbB4 receptors. 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.
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影响因子：
8.8
作者：
Dey S;Banker G;Ray K
通讯作者：
Ray K
影响因子：
7.8
作者：
Bao, JX;Wolpowitz, D;Role, LW;Talmage, DA
通讯作者：
Talmage, DA
影响因子：
15.1
作者：
Buggia-Prévot V;Fernandez CG;Riordan S;Vetrivel KS;Roseman J;Waters J;Bindokas VP;Vassar R;Thinakaran G
通讯作者：
Thinakaran G
影响因子：
16.2
作者：
Farías GG;Cuitino L;Guo X;Ren X;Jarnik M;Mattera R;Bonifacino JS
通讯作者：
Bonifacino JS
DOI：
10.1002/ajmg.b.32552
发表时间：
2018-03
期刊：
American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics
影响因子：
--
作者：
Avramopoulos D
通讯作者：
Avramopoulos D