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

Cell Rep. 2021 Sep 14;36(11):109694. doi: 10.1016/j.celrep.2021.109694.

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.

Keywords: Drosophila; HP1; Lamin; PIN1; heterochromatin; mechanical stress; neurodegeneration; nuclear envelope; phosphorylation; transposons.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Animals
  • Cells, Cultured
  • Chromobox Protein Homolog 5 / genetics
  • Chromobox Protein Homolog 5 / metabolism
  • DNA Transposable Elements / genetics
  • Drosophila / metabolism
  • Drosophila Proteins / antagonists & inhibitors
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Heterochromatin / metabolism*
  • Humans
  • Lamin Type B / chemistry
  • Lamin Type B / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • NIMA-Interacting Peptidylprolyl Isomerase / antagonists & inhibitors
  • NIMA-Interacting Peptidylprolyl Isomerase / genetics
  • NIMA-Interacting Peptidylprolyl Isomerase / metabolism*
  • Neocortex / cytology
  • Neocortex / metabolism
  • Neurons / cytology
  • Neurons / metabolism
  • Nuclear Envelope / chemistry
  • Peptidylprolyl Isomerase / antagonists & inhibitors
  • Peptidylprolyl Isomerase / genetics
  • Peptidylprolyl Isomerase / metabolism*
  • Phosphorylation
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Stress, Mechanical*

Substances

  • DNA Transposable Elements
  • Drosophila Proteins
  • Heterochromatin
  • Lamin Type B
  • NIMA-Interacting Peptidylprolyl Isomerase
  • RNA, Small Interfering
  • Chromobox Protein Homolog 5
  • Peptidylprolyl Isomerase
  • dod protein, Drosophila