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primary topic: Spatiotemporal regulation of ligand trafficking and TLR9 activation by PIEZO1 in human plasmacytoid dendritic cells

Spatiotemporal regulation of ligand trafficking and TLR9 activation by PIEZO1 in human plasmacytoid dendritic cells
type: AcademicArticle
type: Article
abstract: Plasmacytoid dendritic cells (pDCs) are innate immune cells that produce type I interferons (IFNs) upon sensing nucleic acids via Toll-like receptor 9 (TLR9). Synthetic oligodeoxynucleotides CpGA and CpGB are widely used TLR9 agonists, yet only CpGA robustly induces IFN-α in pDCs. In contrast, CpGB drives much less IFN production. The mechanism underlying this ligand-specific response is not known. Here, we identify PIEZO1, a mechanosensory ion channel, as a regulator for this ligand-specific response. We show that CpGA, unlike CpGB, self-associates into large aggregates that generate membrane tension during cellular uptake, activating PIEZO1. This triggers calcium influx and localized F-actin assembly, retaining CpGA in early endosomes to sustain IRF7 activation and IFN production. PIEZO1 deficiency or inhibition abolishes CpGA-induced IFN responses, while PIEZO1 activation enhances IFN production by CpGB. Our findings reveal a hitherto unknown biophysical checkpoint in TLR9 signaling, where PIEZO1 translates membrane tension into spatially controlled TLR9 signaling. This study uncovers a novel role for mechanosensing in nucleic acid immunity, with implications for modulating IFN responses in infections and autoimmunity.
date: 2026-01
volume: 9
issue: resear
status: peerReviewed
status: published
author list: authors
type: EPrint
type: ArticleEPrint
is part of: repository
subject: QR Microbiology

American Association for the Advancement of Science (AAAS)
type: Organization

Research (Wash. D.C.)
type: Collection

Nidhi Kalidas
type: Person
given name: Nidhi
family name: Kalidas

Krishnananda Chattopadhyay
type: Person
given name: Krishnananda
family name: Chattopadhyay

Tithi Mandal
type: Person
given name: Tithi
family name: Mandal

Dipyaman Ganguly
type: Person
given name: Dipyaman
family name: Ganguly

Upasana Mukhopadhyay
type: Person
given name: Upasana
family name: Mukhopadhyay

Shrestha Pattanayak
type: Person
given name: Shrestha
family name: Pattanayak

Deblina Raychaudhuri
type: Person
given name: Deblina
family name: Raychaudhuri

Chinky Shiu Chen Liu
type: Person
given name: Chinky Shiu Chen
family name: Liu

Fnu Ashish
type: Person
given name: Fnu
family name: Ashish

Sumangal Roychowdhury
type: Person
given name: Sumangal
family name: Roychowdhury

Bidisha Sinha
type: Person
given name: Bidisha
family name: Sinha

Purbita Bandopadhyay
type: Person
given name: Purbita
family name: Bandopadhyay

HTML Summary of #3206 Spatiotemporal regulation of ligand trafficking and TLR9 activation by PIEZO1 in human plasmacytoid dendritic cells
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primary topic: Spatiotemporal regulation of ligand trafficking and TLR9 activation by PIEZO1 in human plasmacytoid dendritic cells

QR Microbiology
type: Concept