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WTAP-Mediated m6A Modification of TRAIL-DR4 Suppresses MH7A Cell Apoptosis

Xiaoya Cui1,2, Fengxia Xu1,3, Xue Pang1,3

  • 1The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui, China.

International Journal of Rheumatic Diseases
|January 11, 2025
PubMed
Abstract

Insights

Wilms tumor 1-associating protein (WTAP) epigenetically modifies TNF-related apoptosis-inducing ligand death receptor 4 (TRAIL-DR4) mRNA, suppressing apoptosis in rheumatoid arthritis (RA) cells. This finding reveals a novel therapeutic target for RA treatment.

Area of Science:

  • Epigenetics and RNA modification
  • Molecular mechanisms of autoimmune diseases

Background:

  • N6-methyladenosine (m6A) is a crucial RNA modification involved in biological processes like apoptosis and proliferation.
  • Wilms tumor 1-associating protein (WTAP) is a key m6A regulator implicated in cell proliferation and apoptosis.
  • The role of WTAP in rheumatoid arthritis (RA), characterized by synovial hyperplasia, remains largely unexplored.

Purpose of the Study:

  • To investigate the role of WTAP-mediated m6A modification of TNF-related apoptosis-inducing ligand death receptor 4 (TRAIL-DR4) in RA.
  • To elucidate the impact of WTAP on cellular processes in RA synovial cells.

Main Methods:

  • WTAP overexpression and silencing in MH7A cells using plasmids and small interfering RNAs.
  • Assessment of gene and protein expression (WTAP, BCL2, BAX, TRAIL-DR4) via immunofluorescence, RT-qPCR, and Western blot.
  • Evaluation of cell viability, cell cycle, apoptosis, and proliferation using CCK-8, flow cytometry, and TEM.
  • Verification of TRAIL-DR4 m6A modification and mRNA stability using MeRIP-qPCR and actinomycin D assays.

Main Results:

  • WTAP overexpression increased WTAP and BCL2 levels, decreased BAX and TRAIL-DR4 levels, inhibited apoptosis, and promoted cell viability and proliferation in MH7A cells.
  • WTAP silencing yielded opposite effects, highlighting WTAP's pro-survival role.
  • WTAP was found to promote TRAIL-DR4 m6A modification, reduce TRAIL-DR4 mRNA stability, and subsequently inhibit apoptosis.

Conclusions:

  • WTAP-mediated m6A modification of TRAIL-DR4 suppresses apoptosis in RA synovial cells (MH7A).
  • This mechanism provides a novel therapeutic target for RA.
  • The findings expand the understanding of RA pathophysiology through the lens of m6A alterations.
Keywords:
N6‐methyladenosineTRAIL‐DR4WTAPfibroblast‐like synoviocytesrheumatoid arthritis

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