BNIP-H Recruits the Cholinergic Machinery to Neurite Terminals to Promote Acetylcholine Signaling and Neuritogenesis.
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.
Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore; Mechanobiology Institute Singapore, National University of Singapore, Singapore 117411, Singapore.
Jichao
J
Sun
Mechanobiology Institute Singapore, National University of Singapore, Singapore 117411, Singapore.
Catherine Qiurong
CQ
Pan
Mechanobiology Institute Singapore, National University of Singapore, Singapore 117411, Singapore.
Ti Weng
TW
Chew
Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore.
Fengyi
F
Liang
The Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109-5720, USA; Department of Psychiatry, University of Michigan, Ann Arbor, MI 48109-2700, USA; Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109-5618, USA.
Margit
M
Burmeister
Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore; Mechanobiology Institute Singapore, National University of Singapore, Singapore 117411, Singapore. Electronic address: dbslowbc@nus.edu.sg.
Boon Chuan
BC
Low
D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D018678:Cholinergic Agents / Q000494:pharmacology; D016547:Kinesins; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D016501:Neurites / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology
D018678:Cholinergic Agents; C000715688:KLC1 protein, human; C000715690:Klc1 protein, rat; C000715695:Kns2 protein, mouse; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; C508764:atcay protein, rat; D002795:Choline O-Acetyltransferase; D016547:Kinesins; D000109:Acetylcholine