Conserved Lysine Acetylation within the Microtubule-Binding Domain Regulates MAP2/Tau Family Members.

Andrew W Hwang,Ronen Marmorstein,Virginia M Y Lee,Dave Friedmann,Hanna Trzeciakiewicz,Chao-Xing Yuan,Todd J Cohen,Emmanuel Planel

doi:10.1371/journal.pone.0168913

Abstract

Lysine acetylation has emerged as a dominant post-translational modification (PTM) regulating tau proteins in Alzheimer’s disease (AD) and related tauopathies. Mass spectrometry studies indicate that tau acetylation sites cluster within the microtubule-binding region (MTBR), a region that is highly conserved among tau, MAP2, and MAP4 family members, implying that acetylation could represent a conserved regulatory mechanism for MAPs beyond tau. Here, we combined mass spectrometry, biochemical assays, and cell-based approaches to demonstrate that the tau family members MAP2 and MAP4 are also subject to reversible acetylation. We identify a cluster of lysines in the MAP2 and MAP4 MTBR that undergo CBP-catalyzed acetylation, many of which are conserved in tau. Similar to tau, MAP2 acetylation can occur in a cysteine-dependent auto-regulatory manner in the presence of acetyl-CoA. Furthermore, tubulin reduced MAP2 acetylation, suggesting tubulin binding dictates MAP acetylation status. Taken together, these results uncover a striking conservation of MAP2/Tau family post-translational modifications that could expand our understanding of the dynamic mechanisms regulating microtubules.

Highlights

The microtubule (MT)-associated protein (MAP) tau is expressed primarily in the nervous system, in which six tau isoforms exist containing either three (3R-tau) or four (4R-tau) MTbinding repeat domains
MAP2/Tau family members are subject to lysine acetylation
We provide the first evidence for conserved lysine acetylation as a mechanism regulating MAP2/Tau family members

Summary

Introduction

The microtubule (MT)-associated protein (MAP) tau is expressed primarily in the nervous system, in which six tau isoforms exist containing either three (3R-tau) or four (4R-tau) MTbinding repeat domains. Along with the flanking regions, the MT-binding domains coordinate tau-MT binding and stabilization [1, 2]. Over the last several years, we and others demonstrated that tau is subject to lysine acetylation mainly within the MT-binding repeat region (MTBR), identifying a new and emerging post-translational modification (PTM) that could dominantly regulate multiple aspects of tau function [3,4,5,6,7]. Inc. The funder provided support in the form of salaries for CXY, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. None of the other funders had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific role of this author is articulated in the ‘author contributions’ section

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Conclusion