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Threonine 150 Phosphorylation of Keratin 5 Is Linked to Epidermolysis Bullosa Simplex and Regulates Filament Assembly and Cell Viability

Lookup NU author(s): Professor Boguslaw Obara

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This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).


Abstract

© 2017 The Authors. A characteristic feature of the skin blistering disease epidermolysis bullosa simplex is keratin filament (KF) network collapse caused by aggregation of the basal epidermal keratin type II (KtyII) K5 and its type I partner keratin 14 (K14). Here, we examine the role of keratin phosphorylation in KF network rearrangement and cellular functions. We detect phosphorylation of the K5 head domain residue T150 in cytoplasmic epidermolysis bullosa simplex granules containing R125C K14 mutants. Expression of phosphomimetic T150D K5 mutants results in impaired KF formation in keratinocytes. The phenotype is enhanced upon combination with other phosphomimetic K5 head domain mutations. Remarkably, introduction of T150D K5 mutants into KtyII-lacking (KtyII –/– ) keratinocytes prevents keratin network formation altogether. In contrast, phosphorylation-deficient T150A K5 leads to KFs with reduced branching and turnover. Assembly of T150D K5 is arrested at the heterotetramer stage coinciding with increased heat shock protein association. Finally, reduced cell viability and elevated response to stressors is noted in T150 mutant cells. Taken together, our findings identify T150 K5 phosphorylation as an important determinant of KF network formation and function with a possible role in epidermolysis bullosa simplex pathogenesis.


Publication metadata

Author(s): Sawant M, Schwarz N, Windoffer R, Magin TM, Krieger J, Mucke N, Obara B, Jankowski V, Jankowski J, Wally V, Lettner T, Leube RE

Publication type: Article

Publication status: Published

Journal: Journal of Investigative Dermatology

Year: 2018

Volume: 138

Issue: 3

Pages: 627-636

Print publication date: 01/03/2018

Online publication date: 06/12/2017

Acceptance date: 08/10/2017

Date deposited: 04/05/2021

ISSN (print): 0022-202X

ISSN (electronic): 1523-1747

Publisher: Elsevier BV

URL: https://doi.org/10.1016/j.jid.2017.10.011

DOI: 10.1016/j.jid.2017.10.011

PubMed id: 29080682


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