Inhibitor of DNA binding 2 (Id2) mediates microtubule polymerization in the brain by regulating \u03b1K40 acetylation of \u03b1-tubulin

Taegwan Yun,Jihoe Kim,Kye Won Park,Jee-Yin Ahn,Hyo Rim Ko,Dong-Gyu Jo,Sung-Woo Cho

doi:10.1038/s41420-021-00652-4

Abstract

Acetylation of α-tubulin lysine 40 (αK40) contributes to microtubule (MT) stability and is essential for neuronal development and function, whereas excessive αK40 deacetylation is observed in neurodegenerative disorders including Alzheimer’s disease (AD). Here we identified inhibitor of DNA binding 2 (Id2) as a novel MT-binding partner that interacts with α-tubulin and enhances αK40 acetylation, leading to MT polymerization in the neurons. Commensurate with our finding that the low levels of Id2 expression along with a reduced αK40 acetylation in the postmortem human AD patient and 5X-FAD, AD model mice brain, Id2 upregulation in the hippocampus of 5X-FAD, which exhibit high levels of Sirt2 expression, increased αK40 acetylation and reconstitutes axon growth. Hence our study suggests that Id2 is critical for maintaining MT stability during neural development and the potential of Id2 to counteract pathogenic Sirt2 activity in AD.

Highlights

Inhibitor of DNA binding 2 (Id2) is a negative regulator of basic helix–loop–helix transcription factors
In postmortem brain of Alzheimer’s disease (AD) patients and hippocampus of AD model (5X-FAD) mice, we found that notably diminished levels of Id2 compared to age-matched control, implying the reduction of Id2 is correlated with impaired MT stability
Id2 interacts with α-tubulin in the developing brain Because Id2 localized both at the peripheral domain of growth cone, binding to F-actin when phosphorylated by Akt and at the central domain of axon shaft [5, 6], we speculated that Id2 may contribute to the regulation of MT dynamics by cross-linking the actin-cytoskeleton

Summary

Introduction

Inhibitor of DNA binding 2 (Id2) is a negative regulator of basic helix–loop–helix (bHLH) transcription factors. Id2 binding to bHLH transcription factors suppresses the expression of several growth inhibitory molecules, promoting axon growth [1]. Id2 degradation in the brain by the anaphasepromoting complex/cyclosome and its activator Cdh (APC/ CCdh1) reduces E protein-dependent axonal growth, maintaining axon morphology [2, 3], while Id2 protection results in erratic growth and abnormal distribution of parallel fibers in the cerebral cortex [4]. We have recently demonstrated that Id2 phosphorylation at serine 14 (S14) by Akt enhances axonal growth and growth cone formation in developing neurons by controlling actin-cytoskeleton dynamics [5, 6]. The role of αK40 acetylation has been obtained mainly by manipulating the αK40 acetyltransferase αTAT1/MEC-17 or the deacetylases Sirt and HDAC6. HDAC6 is another major α-tubulin deacetylase in some cells [20, 21], but tubulin is not hyperacetylated in the brains of HDAC6 deficient mice [22]

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