Alternative translation initiation produces synaptic organizer proteoforms with distinct localization and functions.

Autor:	Lee PJ; Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06510, USA; Interdepartmental Neuroscience Program, Yale University, New Haven, CT 06520, USA., Sun Y; Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06510, USA., Soares AR; Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06508, USA; Interdepartmental Neuroscience Program, Yale University, New Haven, CT 06520, USA., Fai C; Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06508, USA., Picciotto MR; Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06508, USA; Interdepartmental Neuroscience Program, Yale University, New Haven, CT 06520, USA., Guo JU; Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06510, USA; Interdepartmental Neuroscience Program, Yale University, New Haven, CT 06520, USA. Electronic address: junjie.guo@yale.edu.
Jazyk:	angličtina
Zdroj:	Molecular cell [Mol Cell] 2024 Oct 17; Vol. 84 (20), pp. 3967-3978.e8. Date of Electronic Publication: 2024 Sep 23.
DOI:	10.1016/j.molcel.2024.08.032
Abstrakt:	While many mRNAs contain more than one translation initiation site (TIS), the functions of most alternative TISs and their corresponding protein isoforms (proteoforms) remain undetermined. Here, we showed that alternative usage of CUG and AUG TISs in neuronal pentraxin receptor (NPR) mRNA produced two proteoforms, of which the ratio was regulated by RNA secondary structure and neuronal activity. Downstream AUG initiation truncated the N-terminal transmembrane domain and produced a secreted NPR proteoform sufficient in promoting synaptic clustering of AMPA-type glutamate receptors. Mutations that altered the ratio of NPR proteoforms reduced AMPA receptors in parvalbumin-positive interneurons and affected learning behaviors in mice. In addition to NPR, upstream AUU-initiated N-terminal extension of C1q-like synaptic organizers anchored these otherwise secreted factors to the membrane. Together, these results uncovered the plasticity of N-terminal signal sequences regulated by alternative TIS usage as a potentially widespread mechanism in diversifying protein localization and functions. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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