SIRT2 deacetylates GRASP55 to facilitate post-mitotic Golgi assembly

Abstract

Sirtuin 2 (SIRT2) is an NAD-dependent sirtuin deacetylase that regulates microtubule and chromatin dynamics, gene expression and cell cycle progression, as well as nuclear envelope reassembly. Recent proteomic analyses have identified Golgi proteins as SIRT2 interactors, indicating that SIRT2 may also play a role in Golgi structure formation. Here, we show that SIRT2 depletion causes Golgi fragmentation and impairs Golgi reassembly at the end of mitosis. SIRT2 interacts with the Golgi reassembly stacking protein GRASP55 (also known as GORASP2) in mitosis when GRASP55 is highly acetylated on K50. Expression of wild-type and the K50R acetylation-deficient mutant of GRASP55, but not the K50Q acetylation-mimetic mutant, in GRASP55 and GRASP65 (also known as GORASP1) double-knockout cells, rescued the Golgi structure and post-mitotic Golgi reassembly. Acetylation-deficient GRASP55 exhibited a higher self-interaction efficiency, a property required for Golgi structure formation. These results demonstrate that SIRT2 regulates Golgi structure by modulating GRASP55 acetylation levels.

Morphological determination of localization and function of Golgi proteins

“…A stack, on the other hand, refers to multiple flattened cisternae that are piled up together. Using ImageJ, the length of the longest cisternae within a Golgi stack was measured, while the number of cisternae layers in the Golgi stack with the highest quantity was counted as the number of cisternae per stack in a cell (Zhang et al 2019a ). In the experiments comparing the Golgi in HeLa WT and VCIP135 KD cells, the abnormalities in Golgi stack formation were characterized by (1) a decreased number of cisternae per stack, and (2) a reduced length of the cisternae within each stack (Zhang et al 2014 ).…”

Golgi defect as a major contributor to lysosomal dysfunction

“…The role of GRASP55 in Golgi stacking is also regulated by Sirtuin 2 (SIRT2) ( Zhang et al, 2019a ), a NAD-dependent sirtuin deacetylase that involves various cellular processes, such as microtubule and chromatin dynamics, gene expression, cell cycle progression, and nuclear envelope reassembly ( North et al, 2003 ; Pandithage et al, 2008 ; Janke, 2014 ; Kaufmann et al, 2016 ). Depletion of SIRT2 in cells induces Golgi fragmentation and impairs Golgi reassembly at the end of mitosis due to acetylation of GRASP55 ( Zhang et al, 2019a ). During mitosis, SIRT2 interacts with highly acetylated GRASP55, regulating its acetylation levels.…”

Sirtuin 2 (SIRT2): Confusing Roles in the Pathophysiology of Neurological Disorders

“…Another study corroborated that the mutation of serine 368 in SIRT2 reduces hyperploidy in cells under mitotic stress in the presence of microtubule poisons, while SIRT2 overexpression mediates a delay in cellular proliferation by enhancing the level of serine 368 phosphorylation ( North and Verdin, 2007b ). SIRT2 also affects mitosis by triggering Golgi fragmentation and impairing Golgi assembly ( Zhang et al, 2019 ). SIRT2 deficiency or overexpression results in impairments in nuclear envelope reassembly and acetylation as well as phosphorylation of the ankyrin repeat and LEM domain containing 2 (ANKLE2) throughout the cell cycle ( Kaufmann et al, 2016 ).…”