Transcription factor Creb3l1 maintains proteostasis in neuroendocrine cells

Mingkwan Greenwood, Benjamin T Gillard, Rizwan Farrukh, Alex Paterson, Ferdinand Althammer, Valery Grinevich, David Murphy, Michael P Greenwood

Research output: Contribution to journalArticle (Academic Journal)peer-review

5 Citations (Scopus)
94 Downloads (Pure)

Abstract

Objectives
Dynamic changes to neuropeptide hormone synthesis and secretion by hypothalamic neuroendocrine cells is essential to ensure metabolic homeostasis. The specialised molecular mechanisms that allow neuroendocrine cells to synthesise and secrete vast quantities of neuropeptides remain ill defined. The objective of this study was to identify novel genes and pathways controlled by transcription factor and endoplasmic reticulum stress sensor Creb3l1 which is robustly activated in hypothalamic magnocellular neurones in response to increased demand for protein synthesis.

Methods
We adopted a multiomic strategy to investigate specific roles of Creb3l1 in rat magnocellular neurones. We first performed chromatin immunoprecipitation followed by genome sequencing (ChIP-seq) to identify Creb3l1 genomic targets and then integrated this data with RNA sequencing data from physiologically stimulated and Creb3l1 knockdown magnocellular neurones.

Results
The data converged on Creb3l1 targets that code for ribosomal proteins and endoplasmic reticulum proteins crucial for the maintenance of cellular proteostasis. We validated genes that compose the PERK arm of the unfolded protein response pathway including Eif2ak3, Eif2s1, Atf4 and Ddit3 as direct Creb3l1 targets. Importantly, knockdown of Creb3l1 in the hypothalamus led to a dramatic depletion in neuropeptide synthesis and secretion. The physiological outcomes from studies of paraventricular and supraoptic nuclei Creb3l1 knockdown animals were changes to food and water consumption.

Conclusion
Collectively, our data identify Creb3l1 as a comprehensive controller of the PERK signalling pathway in magnocellular neurones in response to physiological stimulation. The broad regulation of neuropeptide synthesis and secretion by Creb3l1 presents a new therapeutic strategy for metabolic diseases.
Original languageEnglish
Article number101542
Pages (from-to)1-17
JournalMolecular metabolism
Volume63
Early online date6 Jul 2022
DOIs
Publication statusPublished - 1 Sept 2022

Bibliographical note

Funding Information:
This research was supported by the Medical Research Council (Grant MR/N022807/1 ) to MG, DM, and MPG. BTG was supported by the Biotechnology and Biological Sciences Research Council-SWBio DTP programme ( BBSRC BB/M009122/1 ). VG was supported by the German Research Foundation grants GR 3619/15-1 , GR 3619/16-1 , and SFB Consortium 1158-2.

Publisher Copyright:
© 2022 The Author(s)

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