EEF1A1 deacetylation enables transcriptional activation of remyelination

Mert Duman,Devanarayanan Siva Sankar,Claire Jacob,Manfred Heller,Thomas Zeis,Adrien Vaquié,Antoinette Hayoz,Nicole Schaeren-Wiemers,Jörn Dengjel,Gianluigi Nocera,Michael Stumpe,Patrick Matthias,Dies Meijer,Sophie Ruff,Teppei Yamaguchi

doi:10.1038/s41467-020-17243-z

Abstract

Remyelination of the peripheral and central nervous systems (PNS and CNS, respectively) is a prerequisite for functional recovery after lesion. However, this process is not always optimal and becomes inefficient in the course of multiple sclerosis. Here we show that, when acetylated, eukaryotic elongation factor 1A1 (eEF1A1) negatively regulates PNS and CNS remyelination. Acetylated eEF1A1 (Ac-eEF1A1) translocates into the nucleus of myelinating cells where it binds to Sox10, a key transcription factor for PNS and CNS myelination and remyelination, to drag Sox10 out of the nucleus. We show that the lysine acetyltransferase Tip60 acetylates eEF1A1, whereas the histone deacetylase HDAC2 deacetylates eEF1A1. Promoting eEF1A1 deacetylation maintains the activation of Sox10 target genes and increases PNS and CNS remyelination efficiency. Taken together, these data identify a major mechanism of Sox10 regulation, which appears promising for future translational studies on PNS and CNS remyelination.

Highlights

Remyelination of the peripheral and central nervous systems (PNS and CNS, respectively) is a prerequisite for functional recovery after lesion
We previously showed that HDAC1 and HDAC2, which can compensate for the loss of each other, are necessary for Sox[10] functions in the PNS, and that HDAC2 is primarily involved in this process[38,39,41]
We found strongly increased levels of Ac-eEF1A in Schwann cells (SCs) of postnatal day (P)[4] DhhCre;Hdac1fl/fl;Hdac2fl/fl knockout nerves as compared to Dhh-Cre-negative control littermates (Fig. 1b, c), while total eukaryotic elongation factor 1A1 (eEF1A1) levels were similar in control and dKO nerves (Fig. 1d), indicating that eEF1A deacetylation depends on HDAC1/2 in SCs

Summary

Introduction

Remyelination of the peripheral and central nervous systems (PNS and CNS, respectively) is a prerequisite for functional recovery after lesion This process is not always optimal and becomes inefficient in the course of multiple sclerosis. Promoting eEF1A1 deacetylation maintains the activation of Sox[10] target genes and increases PNS and CNS remyelination efficiency. Posttranslational modifications including acetylation and methylation have been recently shown to hold critical functions in regulating transcription factor activity and gene expression during myelination and remyelination[19,20,21]. HDAC1, HDAC3, and HDAC10 can promote nuclear localization of the transcription factor Olig[1] by deacetylation and thereby OL maturation[23] Methylation marks, such as trimethylation of histone H3 lysine 4 (H3K4me3), are involved in the myelination process. In the context of remyelination, HDAC2 allows the recruitment of a multifunctional protein complex containing Sox[10] and the two

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Conclusion