Phase-separated protein droplets of amyotrophic lateral sclerosis-associated p62/SQSTM1 mutants show reduced inner fluidity

Mohammad Omar, Faruk

doi:https://doi.org/10.1016/j.jbc.2021.101405

WEKO3

lat lon distance

[[sub_check.contents]]

[[sub_radio.contents]]

Field does not validate

[[sub_attr.contents]]　

インデックスツリー

アイテム

筋萎縮性側索硬化症に関連するp62/SQSTM1変異体が形成する相分離液滴は内部流動性が低下している

http://hdl.handle.net/10191/0002000868

名前 / ファイル	ライセンス	アクション
本文 (4.1MB)
要旨 (256KB)

Item type

学位論文 / Thesis or Dissertation(1)

公開日

2023-03-07

タイトル

Phase-separated protein droplets of amyotrophic lateral sclerosis-associated p62/SQSTM1 mutants show reduced inner fluidity

言語

タイトル

筋萎縮性側索硬化症に関連するp62/SQSTM1変異体が形成する相分離液滴は内部流動性が低下している

言語

eng

キーワード

言語

主題Scheme

Other

主題

p62

キーワード

言語

主題Scheme

Other

主題

liquid droplet

キーワード

言語

主題Scheme

Other

主題

amyotrophic lateral sclerosis

キーワード

言語

主題Scheme

Other

主題

autophagy

キーワード

言語

主題Scheme

Other

主題

NRF2

資源タイプ

資源タイプ識別子

http://purl.org/coar/resource_type/c_db06

資源タイプ

doctoral thesis

アクセス権

open access

アクセス権URI

http://purl.org/coar/access_right/c_abf2

その他のタイトル

Characterization of disease-related p62 droplets

言語

著者

Mohammad Omar, Faruk

抄録

内容記述タイプ

Abstract

内容記述

Several amyotrophic lateral sclerosis (ALS)-related proteins such as FUS, TDP-43, and hnRNPA1 demonstrate liquid-liquid phase separation, and their disease-related mutations correlate with a transition of their liquid droplet form into aggregates. Missense mutations in SQSTM1/p62, which have been identified throughout the gene, are associated with ALS, frontotemporal degeneration (FTD), and Paget's disease of bone. SQSTM1/p62 protein forms liquid droplets through interaction with ubiquitinated proteins, and these droplets serve as a platform for autophagosome formation and the anti-oxidative stress response via the LC3-interacting region (LIR) and KEAP1-interacting region (KIR) of p62, respectively. However, it remains unclear whether ALS/FTD-related p62 mutations in the LIR and KIR disrupt liquid droplet formation leading to defects in autophagy, the stress response, or both. To evaluate the effects of ALS/FTD-related p62 mutations in the LIR and KIR on a major oxidative stress system, the Keap1-Nrf2 pathway, as well as on autophagic turnover, we developed systems to monitor each of these with high sensitivity. These methods such as intracellular protein-protein interaction assay, doxycycline-inducible gene expression system and gene expression into primary cultured cells with recombinant adenovirus revealed that some mutants, but not all, caused reduced NRF2 activation and delayed autophagic cargo turnover. In contrast, while all p62 mutants demonstrated sufficient ability to form liquid droplets, all of these droplets also exhibited reduced inner fluidity. These results indicate that like other ALS-related mutant proteins, p62 missense mutations result in a primary defect in ALS/FTD via a qualitative change in p62 liquid droplet fluidity.

言語

内容記述

内容記述タイプ

Other

内容記述

The Journal of biological chemistry. 2021, 297(6), 101405.

言語

DOI

識別子タイプ

DOI

Versions

Ver.1

2023-03-07 05:15:09.121167

Show All versions

Cite as

エクスポート

OAI-PMH

JPCOAR 2.0
JPCOAR 1.0
DublinCore
DDI

Other Formats

JSON
BIBTEX

インデックスリンク

インデックスツリー

アイテム

筋萎縮性側索硬化症に関連するp62/SQSTM1変異体が形成する相分離液滴は内部流動性が低下している

× Mohammad Omar, Faruk

Versions

Share

Cite as

エクスポート