title: Loss of the Ubiquitin-conjugating Enzyme UBE2W Results in Susceptibility to Early Postnatal Lethality and Defects in Skin, Immune, and Male Reproductive Systems.
abstract: UBE2W ubiquitinates N termini of proteins rather than internal lysine residues, showing a preference for substrates with intrinsically disordered N termini. The in vivo functions of this intriguing E2, however, remain unknown. We generated Ube2w germ line KO mice that proved to be susceptible to early postnatal lethality without obvious developmental abnormalities. Although the basis of early death is uncertain, several organ systems manifest changes in Ube2w KO mice. Newborn Ube2w KO mice often show altered epidermal maturation with reduced expression of differentiation markers. Mirroring higher UBE2W expression levels in testis and thymus, Ube2w KO mice showed a disproportionate decrease in weight of these two organs (~50%), suggesting a functional role for UBE2W in the immune and male reproductive systems. Indeed, Ube2w KO mice displayed sustained neutrophilia accompanied by increased G-CSF signaling and testicular vacuolation associated with decreased fertility. Proteomic analysis of a vulnerable organ, presymptomatic testis, showed a preferential accumulation of disordered proteins in the absence of UBE2W, consistent with the view that UBE2W preferentially targets disordered polypeptides. These mice further allowed us to establish that UBE2W is ubiquitously expressed as a single isoform localized to the cytoplasm and that the absence of UBE2W does not alter cell viability in response to various stressors. Our results establish that UBE2W is an important, albeit not essential, protein for early postnatal survival and normal functioning of multiple organ systems.
authors.affiliation: From the Departments of Neurology, Neuroscience Graduate Program, and.
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.affiliation: From the Departments of Neurology.
authors.forename: Sean A
authors.initials: SA
authors.lastname: Merillat
authors.affiliation: Molecular and Integrative Physiology and Computational Medicine and Bioinformatics.
authors.forename: Michael
authors.initials: M
authors.lastname: Vincent
authors.affiliation: From the Departments of Neurology.
authors.forename: Amanda K
authors.initials: AK
authors.lastname: Huber
authors.affiliation: Pathology, and.
authors.forename: Venkatesha
authors.initials: V
authors.lastname: Basrur
authors.affiliation: Dermatology.
authors.forename: Doris
authors.initials: D
authors.lastname: Mangelberger
authors.affiliation: From the Departments of Neurology.
authors.forename: Li
authors.initials: L
authors.lastname: Zeng
authors.affiliation: Pathology, and.
authors.forename: Kojo
authors.initials: K
authors.lastname: Elenitoba-Johnson
authors.affiliation: Pathology and Geriatrics Center, University of Michigan, Ann Arbor, Michigan 48109 and.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Miller
authors.affiliation: From the Departments of Neurology.
authors.forename: David N
authors.initials: DN
authors.lastname: Irani
authors.affiliation: Dermatology.
authors.forename: Andrzej A
authors.initials: AA
authors.lastname: Dlugosz
authors.affiliation: Molecular and Integrative Physiology and Computational Medicine and Bioinformatics.
authors.forename: Santiago
authors.initials: S
authors.lastname: Schnell
authors.affiliation: Department of Biochemistry and Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53226.
authors.forename: Kenneth Matthew
authors.initials: KM
authors.lastname: Scaglione
authors.affiliation: From the Departments of Neurology, henryp@med.umich.edu.
authors.forename: Henry L
authors.initials: HL
authors.lastname: Paulson
mesh_terms: D000818:Animals; D004817:Epidermis / Q000002:abnormalities / Q000201:enzymology / Q000276:immunology; D007960:Leukocyte Disorders / Q000151:congenital / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D012868:Skin Abnormalities / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D013737:Testis / Q000201:enzymology / Q000276:immunology; D013950:Thymus Gland / Q000201:enzymology / Q000276:immunology; D044763:Ubiquitin-Conjugating Enzymes / Q000172:deficiency / Q000276:immunology
chemical_list: C558780:UBE2W protein, mouse; D044763:Ubiquitin-Conjugating Enzymes
keywords: gene knock-out; intrinsically disordered protein; mouse; ubiquitin; ubiquitin-conjugating enzyme (E2 enzyme)