Acetylation of SUMO 2 at lysine 11 favors the formation of non‐canonical SUMO chains

Abstract

Post-translational modifications by ubiquitin-related SUMO modifiers regulate cellular signaling networks and protein homeostasis. While SUMO1 is mainly conjugated to proteins as a monomer, SUMO2/3 can form polymeric chains. Poly-SUMOylation is best understood in the SUMO-targeted ubiquitin ligase (StUbL) pathway, where chains prime proteins for subsequent ubiquitylation by StUbLs. SUMO chains typically form in response to genotoxic or proteotoxic stress and are preferentially linked via lysine 11 of SUMO2/3. Here, we report that K11 of SUMO2/3 undergoes reversible acetylation with SIRT1 being the K11 deacetylase. In a purified system, acetylation of SUMO2/3 impairs chain formation and restricts chain length. In a cellular context, however, K11 acetyl-mimicking SUMO2 does not affect the StUbL pathway, indicating that in cells non-canonical chains are more prevalent. MS-based SUMO proteomics indeed identified non-canonical chain types under basal and stress conditions. Importantly, mimicking K11 acetylation alters chain architecture by favoring K5- and K35-linked chains, while inhibiting K7 and K21 linkages. These data provide insight into SUMO chain signaling and point to a role of K11 acetylation as a modulator of SUMO2/3 chains.

Extensive SUMO Modification of Repressive Chromatin Factors Distinguishes Pluripotent from Somatic Cells

“…Contrarily, in ESCs, the primary linkage was significantly focused on K11, accounting for more than two-thirds of the total SUMO-chain linkages. Of note, acetylation of K11, the prototypical site for SUMO2/3 chain formation ( Tatham et al., 2001 ), was suggested to regulate the formation of non-canonical SUMO2/3 chains ( Gärtner et al., 2018 ). In this regard, it would be interesting to compare K11 acetylation status between the two cell types.…”

SIRT1 Regulates N6‐Methyladenosine RNA Modification in Hepatocarcinogenesis by Inducing RANBP2‐Dependent FTO SUMOylation

“…( 23 ) SUMO acetylation controlled by class I/II Histone deacetylases has been well established for decades, although recent biochemical experiments further uncover that SIRT1 favors SUMO2 chain formation as the K11 deacetylase. ( 27 ) Intriguingly, as one of the crucial nucleoporins, deacetylated RANBP2 may have profound effects on nucleocytoplasmic shuttling of substrates not limited to FTO, and this phenomenon was in consistence with the substrates subcellular localization subjected to acetylation. ( 22 ) The site‐specific deacetylation of E3 ligase RANBP2 by SIRT1 may indicate an intricate crosstalk between the SUMO system and signaling exerted by the protein deacetylase SIRT1 in the nucleus.…”

SUMO and Transcriptional Regulation: The Lessons of Large-Scale Proteomic, Modifomic and Genomic Studies

“…Many proteomics studies have now addressed the precise nature of both SUMOylated proteins and SUMOylated sites at the system-wide level in different species (including mammals, drosophila, worms, plants and yeast), sometimes in pathological situations [ 17 , 21 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 ]. One of their general conclusions is that SUMOylated proteins are largely functionally connected.…”

“…Thus, whereas SUMO-1 cannot form homomeric chains, SUMO-2 and -3 can. This occurs preferably on their lysine 11 (not conserved in SUMO-1), which is part of a SUMOylation consensus site, but can also take place at alternative non-consensus SUMOylation sites [ 73 ]. However, SUMO-1 can be used to cap and terminate SUMO-2/3 chains.…”