SIRT2 regulates nuclear envelope reassembly through ANKLE2 deacetylation

Abstract

Sirtuin 2 (SIRT2) is an NAD-dependent deacetylase known to regulate microtubule dynamics and cell cycle progression. SIRT2 has also been implicated in the pathology of cancer, neurodegenerative diseases and progeria. Here, we show that SIRT2 depletion or overexpression causes nuclear envelope reassembly defects. We link this phenotype to the recently identified regulator of nuclear envelope reassembly ANKLE2. ANKLE2 acetylation at K302 and phosphorylation at S662 are dynamically regulated throughout the cell cycle by SIRT2 and are essential for normal nuclear envelope reassembly. The function of SIRT2 therefore extends beyond the regulation of microtubules to include the regulation of nuclear envelope dynamics.

SIRT2 deacetylates GRASP55 to facilitate post-mitotic Golgi assembly

“…SIRT2 interactomes from MRC5 and HEK293 cells pointed to a new connection between SIRT2 and the ER-Golgi trafficking pathway (Budayeva and Cristea, 2016). Consistent with this, our previous proteomic study revealed ER and Golgi proteins as SIRT2interacting partners (Kaufmann et al, 2016), indicating a role for SIRT2 in ER and Golgi structure formation. To date, the regulation of Golgi structural proteins by acetylation has not been reported.…”

“…Our published SIRT2 interactome revealed that SIRT2 interacts with various Golgi proteins such as GRASP55, Golgin-160 (also known as GOLGA3) and GCP60 (also known as ACBD3) (Kaufmann et al, 2016). GRASP55 ranked second in our previously published interactome analysis and was identified in a proximity biotinylation (BioID) experiment in which SIRT2 was fused to a promiscuous biotin ligase from E. coli (BirA) at both the N-and the C-terminus (Roux et al, 2012).…”

The role of SIRT2 in cancer: A novel therapeutic target

“…15 The K302 bit of the ANKLE2 protein is regulated by SIRT2 deacetylate, which affects the normal assembly of the cell nucleus membrane, interfering with the cell cycle. 44 A growing number of experiments have shown that SIRT2 has a dual role in tumor development, acting as a suppressor or promoter in different cell sources and tumors. 45 In neurogliomas and melanomas, the expression of SIRT2 is significantly reduced.…”

SIRT2 deacetylase regulates the activity of GSK3 isoforms independent of inhibitory phosphorylation

“…SIRT2 is the cytoplasmic deacetylase that affects the microtubule network by deacetylating α-tubulin ( North et al, 2003 ). In addition, SIRT2 regulates nuclear envelope dynamics, cardiac hypertrophy, metabolism and stress-induced cell death ( de Oliveira et al, 2012 ; Kaufmann et al, 2016 ; Sarikhani et al, 2018a ; Sarikhani et al, 2018b ). In neurons, inhibition of SIRT2 salvage α-synuclein toxicity in Parkinson’s disease and reduce sterol-mediated toxicity in Huntington’s disease ( Donmez and Outeiro, 2013 ).…”