title: Functional Crosstalk between the PP2A and SUMO Pathways Revealed by Analysis of STUbL Suppressor, razor 1-1.
abstract: Posttranslational modifications (PTMs) provide dynamic regulation of the cellular proteome, which is critical for both normal cell growth and for orchestrating rapid responses to environmental stresses, e.g. genotoxins. Key PTMs include ubiquitin, the Small Ubiquitin-like MOdifier SUMO, and phosphorylation. Recently, SUMO-targeted ubiquitin ligases (STUbLs) were found to integrate signaling through the SUMO and ubiquitin pathways. In general, STUbLs are recruited to target proteins decorated with poly-SUMO chains to ubiquitinate them and drive either their extraction from protein complexes, and/or their degradation at the proteasome. In fission yeast, reducing or preventing the formation of SUMO chains can circumvent the essential and DNA damage response functions of STUbL. This result indicates that whilst some STUbL "targets" have been identified, the crucial function of STUbL is to antagonize SUMO chain formation. Herein, by screening for additional STUbL suppressors, we reveal crosstalk between the serine/threonine phosphatase PP2A-Pab1B55 and the SUMO pathway. A hypomorphic Pab1B55 mutant not only suppresses STUbL dysfunction, but also mitigates the phenotypes associated with deletion of the SUMO protease Ulp2, or mutation of the STUbL cofactor Rad60. Together, our results reveal a novel role for PP2A-Pab1B55 in modulating SUMO pathway output, acting in parallel to known critical regulators of SUMOylation homeostasis. Given the broad evolutionary functional conservation of the PP2A and SUMO pathways, our results could be relevant to the ongoing attempts to therapeutically target these factors.
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, California, United States of America.
authors.forename: Minghua
authors.initials: M
authors.lastname: Nie
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, California, United States of America.
authors.forename: Emily
authors.identifier: 0000-0003-2394-8681
authors.initials: E
authors.lastname: Arner
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, California, United States of America.
authors.forename: John
authors.initials: J
authors.lastname: Prudden
authors.affiliation: Microarray and Next Generation Sequencing Core Facility, The Scripps Research Institute, La Jolla, California, United States of America.
authors.forename: Lana
authors.initials: L
authors.lastname: Schaffer
authors.affiliation: Microarray and Next Generation Sequencing Core Facility, The Scripps Research Institute, La Jolla, California, United States of America.
authors.forename: Steven
authors.initials: S
authors.lastname: Head
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, California, United States of America.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Boddy
mesh_terms: D002453:Cell Cycle; D049109:Cell Proliferation; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D017353:Gene Deletion; D018628:Gene Dosage; D016681:Genome, Fungal; D005838:Genotype; D049452:Green Fluorescent Proteins / Q000378:metabolism; D009154:Mutation; D010641:Phenotype; D039102:Poly(A)-Binding Proteins / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D012568:Schizosaccharomyces / Q000378:metabolism*; D029702:Schizosaccharomyces pombe Proteins / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism*; D058207:Sumoylation; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D002868:Chromosomal Proteins, Non-Histone; C570818:Pab1 protein, S pombe; D039102:Poly(A)-Binding Proteins; C455501:Rad60 protein, S pombe; D029702:Schizosaccharomyces pombe Proteins; D025841:Small Ubiquitin-Related Modifier Proteins; D049452:Green Fluorescent Proteins; C587431:Slx8 protein, S pombe; D044767:Ubiquitin-Protein Ligases; C000615912:razor 1-1 protein, S pombe; D054648:Protein Phosphatase 2; D046988:Proteasome Endopeptidase Complex