SUMO protease SENP6 protects the nucleus from hyperSUMOylation-induced laminopathy-like alterations

• Published in: Cell reports (Cambridge) Vol. 42; no. 8; p. 112960
• Main Authors: Liczmanska, Magda, Tatham, Michael H., Mojsa, Barbara, Eugui-Anta, Ania, Rojas-Fernandez, Alejandro, Ibrahim, Adel F.M., Hay, Ronald T.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 29.08.2023; Elsevier
• Subjects: CP: Cell biology; CP: Molecular biology; lamin; laminopathy; nuclear blebbing; PISM; proteomics; SENP6; SUMO; SENP6; nuclear blebbing; lamin; SUMO; proteomics; CP: Cell biology; PISM; CP: Molecular biology; laminopathy
• DOI: 10.1016/j.celrep.2023.112960
• ISSN: 2211-1247

The small ubiquitin-like modifier (SUMO) protease SENP6 disassembles SUMO chains from cellular substrate proteins. We use a proteomic method to identify putative SENP6 substrates based on increased apparent molecular weight after SENP6 depletion. Proteins of the lamin family of intermediate filaments show substantially increased SUMO modification after SENP6 depletion. This is accompanied by nuclear structural changes remarkably like those associated with laminopathies. Two SUMO attachment sites on lamin A/C are close to sites of mutations in Emery-Driefuss and limb girdle muscular dystrophy. To establish a direct link between lamin SUMOylation and the observed phenotype, we developed proximity-induced SUMO modification (PISM), which fuses a lamin A/C targeting DARPin to a SUMO E3 ligase domain. This directly targets lamin A/C for SUMO conjugation and demonstrates that enhanced lamin SUMO modification recapitulates the altered nuclear structure manifest after SENP6 depletion. This shows SENP6 activity protects the nucleus against hyperSUMOylation-induced laminopathy-like alterations. [Display omitted] •The SUMO protease SENP6 regulates lamin protein SUMOylation•Sites of SUMOylation in lamin A are close to sites of mutations that cause laminopathies•Depletion of SENP6 leads to laminopathy-type phenotypes in cultured cells•Specific SUMOylation of lamin A can be induced using a DARPin-SUMO-E3 construct The SUMO protease SENP6 preferentially cleaves between SUMO molecules in polySUMO chains. Liczmanska et al. show depletion of SENP6 leads to hyperSUMOylation of lamins A and B and nuclear blebbing reminiscent of laminopathies. Forced hyperSUMOylation of lamins generates the same nuclear phenotype, implying SENP6 functions to suppress adventitious lamin SUMOylation.