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Dysregulation of a lncRNA within the TNFRSF10A locus activates cell death pathways

Tadeusz J Kaczynski1,2, Nadine J Husami1,2,3, Elizabeth D Au2

  • 1Research Service, VA Medical Center, Buffalo, NY, USA.

Cell Death Discovery
|July 13, 2023
PubMed

Insights

The AC100861.1 long noncoding RNA (lncRNA) regulates necroptotic and inflammatory pathways independently of TNFRSF10A. This lncRNA influences cell death under stress, offering insights into disease mechanisms.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Genetics

Background:

  • TNFRSF10A (tumor necrosis factor receptor superfamily member 10A) is a cell surface receptor crucial for apoptosis, necroptosis, and inflammation.
  • Dysregulation of TNFRSF10A is linked to disease development, but the function of the adjacent AC100861.1 long noncoding RNA (lncRNA) remains largely unknown.
  • Genomic proximity suggests a potential functional relationship between AC100861.1 and TNFRSF10A in death receptor signaling.

Purpose of the Study:

  • To investigate the function of the AC100861.1 lncRNA.
  • To determine its relationship with TNFRSF10A.
  • To elucidate its role in death receptor signaling, necroptosis, and inflammation.

Main Methods:

  • Gene knockdown and overexpression strategies were employed for both TNFRSF10A and AC100861.1.
  • Cell viability assays were performed under normal and stressed conditions (tunicamycin).
  • Transcript and protein levels of key apoptosis, necroptosis, and inflammation genes were analyzed. RNA fluorescence in situ hybridization (RNA-FISH) was used for transcript localization.

Main Results:

  • Overexpression of TNFRSF10A or AC100861.1 increased cell death, particularly under cellular stress.
  • Knockdown of TNFRSF10A increased cell death only under stress; AC100861.1 knockdown had no effect on cell death.
  • AC100861.1 manipulation significantly altered expression of necroptosis and inflammatory pathway genes, independent of TNFRSF10A levels.
  • RNA-FISH showed AC100861.1 is predominantly localized in the cytoplasm.

Conclusions:

  • AC100861.1 plays a role in regulating necroptotic and inflammatory signaling pathways.
  • Its function appears distinct from TNFRSF10A expression modulation.
  • AC100861.1's cytoplasmic localization supports its role in post-transcriptional regulation of these pathways.
  • These findings provide insight into a poorly understood lncRNA with potential disease implications.

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