Chromatin organization plays a crucial role in tissue homeostasis. Heterochromatin relaxation and consequent unscheduled mobilization of transposable elements (TEs) are emerging as key contributors of aging and aging-related pathologies, including Alzheimer's disease (AD) and cancer. However, the mechanisms governing heterochromatin maintenance or its relaxation in pathological conditions remain poorly understood. Here we show that PIN1, the only phosphorylation-specific cis/trans prolyl isomerase, whose loss is associated with premature aging and AD, is essential to preserve heterochromatin. We demonstrate that this PIN1 function is conserved from Drosophila to humans and prevents TE mobilization-dependent neurodegeneration and cognitive defects. Mechanistically, PIN1 maintains nuclear type-B Lamin structure and anchoring function for heterochromatin protein 1α (HP1α). This mechanism prevents nuclear envelope alterations and heterochromatin relaxation under mechanical stress, which is a key contributor to aging-related pathologies.

The prolyl-isomerase PIN1 is essential for nuclear Lamin-B structure and function and protects heterochromatin under mechanical stress / F. Napoletano, G. Ferrari Bravo, I.A.P. Voto, A. Santin, L. Celora, E. Campaner, C. Dezi, A. Bertossi, E. Valentino, M. Santorsola, A. Rustighi, V. Fajner, E. Maspero, F. Ansaloni, V. Cancila, C.F. Valenti, M. Santo, O.B. Artimagnella, S. Finaurini, U. Gioia, S. Polo, R. Sanges, C. Tripodo, A. Mallamaci, S. Gustincich, F. d'Adda di Fagagna, F. Mantovani, V. Specchia, G. Del Sal. - In: CELL REPORTS. - ISSN 2211-1247. - 36:11(2021 Sep), pp. 109694.1-109694.17, e1-e12. [10.1016/j.celrep.2021.109694]

The prolyl-isomerase PIN1 is essential for nuclear Lamin-B structure and function and protects heterochromatin under mechanical stress

F. Napoletano
Primo
;
V. Fajner;E. Maspero;S. Finaurini;S. Polo;
2021-09

Abstract

Chromatin organization plays a crucial role in tissue homeostasis. Heterochromatin relaxation and consequent unscheduled mobilization of transposable elements (TEs) are emerging as key contributors of aging and aging-related pathologies, including Alzheimer's disease (AD) and cancer. However, the mechanisms governing heterochromatin maintenance or its relaxation in pathological conditions remain poorly understood. Here we show that PIN1, the only phosphorylation-specific cis/trans prolyl isomerase, whose loss is associated with premature aging and AD, is essential to preserve heterochromatin. We demonstrate that this PIN1 function is conserved from Drosophila to humans and prevents TE mobilization-dependent neurodegeneration and cognitive defects. Mechanistically, PIN1 maintains nuclear type-B Lamin structure and anchoring function for heterochromatin protein 1α (HP1α). This mechanism prevents nuclear envelope alterations and heterochromatin relaxation under mechanical stress, which is a key contributor to aging-related pathologies.
drosophila; heterochromatin; HP1; lamin; mechanical stress; neurodegeneration; nuclear envelope; phosphorylation; PIN1; transposons
Settore MED/04 - Patologia Generale
PRIN201719GSCIT_01 - Role of the YAP/TAZ transcriptional regulators in cancer chemoresistance - SCITA, GIORGIO - PRIN2017 - PRIN bando 2017 - 2019
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/904373
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