BNIP-H Recruits the Cholinergic Machinery to Neurite Terminals to Promote Acetylcholine Signaling and Neuritogenesis

Developmental Cell
Jichao SunBoon Chuan Low

Abstract

Synthesis and release of neurotransmitters such as acetylcholine (ACh) are key to synaptic function. However, little is known about the spatial regulation of their synthesizing machinery. Here, we demonstrate that ataxia-related protein BNIP-H/Caytaxin links kinesin-1 (KLC1) to ATP citrate lyase (ACL), a key enzyme for ACh synthesis, and transports it toward neurite terminals. There, BNIP-H/ACL complex synergistically recruits another enzyme choline acetyltransferase (ChAT), leading to enhanced secretion of ACh. ACh then activates MAPK/ERK via muscarinic receptors to promote neurite outgrowth. In mice deficient in BNIP-H, ACL fails to interact with KLC1, and formation of the ACL/ChAT complex is prevented, whereas the disease-associated BNIP-H mutation fails to target ACL for neurite outgrowth. Significantly, Bnip-h knockdown in zebrafish causes developmental defect in motor neurons through impaired cholinergic pathway, leading to motor disorder. Therefore, precise targeting of the cholinergic machinery through BNIP-H is essential for the local production of ACh for morphogenesis and neurotransmission.

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Citations

Jun 7, 2017·Proceedings of the National Academy of Sciences of the United States of America·Uriya BekensteinHermona Soreq
Jul 28, 2018·Frontiers in Cellular Neuroscience·Anna RonowskaAgnieszka Jankowska-Kulawy
Apr 5, 2019·Nature·Koen H G VerschuerenKenneth Verstraete
Dec 12, 2020·Progress in Biophysics and Molecular Biology·Israel Silman
May 1, 2021·Cells·Ana Quelle-RegaldieLaura Sánchez
May 20, 2021·Proceedings of the National Academy of Sciences of the United States of America·Vishnu Priyanka Reddy ChichiliJ Sivaraman

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