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Transmembrane protein TMEM97 and epigenetic reader BAHCC1 constitute an axis that supports pro-inflammatory cytokine

Jing Li1, Hongtao Shen1, Lian-Wang Guo2

  • 1Division of Surgical Sciences, Department of Surgery, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA.

Cellular Signalling
|January 30, 2024
PubMed

Insights

We discovered a new pathway where TMEM97 protein regulates BAHCC1, which then increases inflammation in retinal pigment epithelium (RPE) cells via NFκB. This finding sheds light on mechanisms behind retinal degenerative diseases.

Area of Science:

  • Ophthalmology
  • Molecular Biology
  • Immunology

Background:

  • Pro-inflammatory cytokine production by retinal pigment epithelium (RPE) is critical in retinal degenerative diseases.
  • The molecular mechanisms driving RPE inflammation remain incompletely understood.
  • TMEM97 and BAHCC1 roles in RPE inflammation were previously unknown.

Purpose of the Study:

  • To investigate the roles of TMEM97 and BAHCC1 in regulating pro-inflammatory cytokine expression in RPE cells.
  • To elucidate the molecular cascade linking TMEM97, BAHCC1, and NFκB in RPE inflammation.

Main Methods:

  • Transcriptomic analysis of TMEM97-/- ARPE19 cells.
  • TMEM97 loss- and gain-of-function studies.
  • Co-immunoprecipitation assays.
  • NFκB pathway analysis.
  • In vivo studies using a mouse model of RPE-damage retinal degeneration.

Main Results:

  • TMEM97 significantly promotes the expression of pro-inflammatory cytokines IL1β and CCL2, and BAHCC1 in RPE cells.
  • TMEM97 and BAHCC1 proteins associate, forming a novel regulatory axis.
  • TMEM97 regulates NFκB activation, a key transcription factor for inflammatory cytokines.
  • Silencing BAHCC1 down-regulates NFκB and downstream cytokines.
  • Tmem97-/- mice exhibit reduced IL1β, CCL2, and glial activation in a retinal degeneration model.

Conclusions:

  • TMEM97 is a novel determinant of pro-inflammatory cytokine expression in RPE.
  • A previously uncharacterized TMEM97 → BAHCC1 → NFκB cascade regulates RPE inflammation.
  • Targeting this pathway may offer therapeutic strategies for retinal degenerative diseases.
Keywords:
BAHCC1NFκBPro-inflammatory cytokinesRetinal pigment epithelial cellTMEM97

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