OTUB1 regulates lung development, adult lung tissue homeostasis, and respiratory control.

Autor: Ruiz-Serrano A; Institute of Physiology, University of Zurich, Zurich, Switzerland., Monné Rodríguez JM; Laboratory for Animal Model Pathology (LAMP), Institute of Veterinary Pathology, University of Zurich, Zurich, Switzerland., Günter J; Institute of Physiology, University of Zurich, Zurich, Switzerland.; National Centre of Competence in Research 'Kidney.CH', Zurich, Switzerland., Sherman SPM; Institute of Physiology, University of Zurich, Zurich, Switzerland., Jucht AE; Institute of Physiology, University of Zurich, Zurich, Switzerland., Fluechter P; Institute of Physiology, University of Zurich, Zurich, Switzerland., Volkova YL; Institute of Physiology, University of Zurich, Zurich, Switzerland., Pfundstein S; Institute of Physiology, University of Zurich, Zurich, Switzerland., Pellegrini G; Laboratory for Animal Model Pathology (LAMP), Institute of Veterinary Pathology, University of Zurich, Zurich, Switzerland., Wagner CA; Institute of Physiology, University of Zurich, Zurich, Switzerland.; National Centre of Competence in Research 'Kidney.CH', Zurich, Switzerland., Schneider C; Institute of Physiology, University of Zurich, Zurich, Switzerland., Wenger RH; Institute of Physiology, University of Zurich, Zurich, Switzerland.; National Centre of Competence in Research 'Kidney.CH', Zurich, Switzerland., Scholz CC; Institute of Physiology, University of Zurich, Zurich, Switzerland.; National Centre of Competence in Research 'Kidney.CH', Zurich, Switzerland.
Jazyk: angličtina
Zdroj: FASEB journal : official publication of the Federation of American Societies for Experimental Biology [FASEB J] 2021 Dec; Vol. 35 (12), pp. e22039.
DOI: 10.1096/fj.202100346R
Abstrakt: OTUB1 is one of the most highly expressed deubiquitinases, counter-regulating the two most abundant ubiquitin chain types. OTUB1 expression is linked to the development and progression of lung cancer and idiopathic pulmonary fibrosis in humans. However, the physiological function of OTUB1 is unknown. Here, we show that constitutive whole-body Otub1 deletion in mice leads to perinatal lethality by asphyxiation. Analysis of (single-cell) RNA sequencing and proteome data demonstrated that OTUB1 is expressed in all lung cell types with a particularly high expression during late-stage lung development (E16.5, E18.5). At E18.5, the lungs of animals with Otub1 deletion presented with increased cell proliferation that decreased saccular air space and prevented inhalation. Flow cytometry-based analysis of E18.5 lung tissue revealed that Otub1 deletion increased proliferation of major lung parenchymal and mesenchymal/other non-hematopoietic cell types. Adult mice with conditional whole-body Otub1 deletion (wbOtub1 del/del ) also displayed increased lung cell proliferation in addition to hyperventilation and failure to adapt the respiratory pattern to hypoxia. On the molecular level, Otub1 deletion enhanced mTOR signaling in embryonic and adult lung tissues. Based on these results, we propose that OTUB1 is a negative regulator of mTOR signaling with essential functions for lung cell proliferation, lung development, adult lung tissue homeostasis, and respiratory regulation.
(© 2021 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)
Databáze: MEDLINE
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