title: Post-translational O-GlcNAcylation is essential for nuclear pore integrity and maintenance of the pore selectivity filter.
abstract: O-glycosylation of the nuclear pore complex (NPC) by O-linked N-acetylglucosamine (O-GlcNAc) is conserved within metazoans. Many nucleoporins (Nups) comprising the NPC are constitutively O-GlcNAcylated, but the functional role of this modification remains enigmatic. We show that loss of O-GlcNAc, induced by either inhibition of O-GlcNAc transferase (OGT) or deletion of the gene encoding OGT, leads to decreased cellular levels of a number of natively O-GlcNAcylated Nups. Loss of O-GlcNAc enables increased ubiquitination of these Nups and their increased proteasomal degradation. The decreased half-life of these deglycosylated Nups manifests in their gradual loss from the NPC and a downstream malfunction of the nuclear pore selective permeability barrier in both dividing and post-mitotic cells. These findings define a critical role of O-GlcNAc modification of the NPC in maintaining its composition and the function of the selectivity filter. The results implicate NPC glycosylation as a regulator of NPC function and reveal the role of conserved glycosylation of the NPC among metazoans.
authors.affiliation: Department of Chemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada.
authors.forename: Yanping
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Chemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada.
authors.forename: Ta-Wei
authors.initials: TW
authors.lastname: Liu
authors.affiliation: Department of Chemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada.
authors.forename: Zarina
authors.initials: Z
authors.lastname: Madden
authors.affiliation: Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Yuzwa
authors.affiliation: Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada.
authors.forename: Kelsey
authors.initials: K
authors.lastname: Murray
authors.affiliation: Department of Chemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada.
authors.forename: Samy
authors.initials: S
authors.lastname: Cecioni
authors.affiliation: Department of Biological Chemistry, Johns Hopkins University Medical School, Baltimore, MD 21205, USA.
authors.forename: Natasha
authors.initials: N
authors.lastname: Zachara
authors.affiliation: Department of Chemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada dvocadlo@sfu.ca.
authors.forename: David J
authors.initials: DJ
authors.lastname: Vocadlo
mesh_terms: D000818:Animals; D002460:Cell Line; D006031:Glycosylation; D051379:Mice; D022022:Nuclear Pore / Q000378:metabolism*; D028861:Nuclear Pore Complex Proteins / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000235:genetics / Q000502:physiology; D055550:Protein Stability; D054875:Ubiquitination / Q000235:genetics / Q000502:physiology
chemical_list: D028861:Nuclear Pore Complex Proteins
keywords: O-GlcNAcylation; glycosylation; nuclear pore complex; nucleoporin; post-translational modification; protein stability; ubiquitination