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Evolutionarily conserved primary TNF sequences relate to its primitive functions in cell death induction.

Wenshu Lu1, Qiongyu Chen1, Songmin Ying1

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Tumor Necrosis Factor (TNF) conserved regions are key to inducing cell death. Specific peptides trigger apoptosis or necrosis, revealing a determinant sequence crucial for TNF's primitive apoptotic function.

Keywords:
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Area of Science:

  • Evolutionary biology
  • Molecular biology
  • Immunology

Background:

  • Tumor Necrosis Factor (TNF) is an ancient protein with a critical role in cellular processes.
  • Understanding TNF's conserved regions is vital for elucidating its functions in health and disease.

Purpose of the Study:

  • To identify conserved regions within TNF across vertebrate taxa.
  • To determine the specific roles of these conserved regions in TNF-induced apoptosis, necrosis, and NF-κB stimulation.

Main Methods:

  • Bioinformatic analysis of TNF sequences from nine vertebrate taxa.
  • Screening of overlapping peptides derived from human TNF.
  • Functional assays to assess apoptosis, necrosis, and NF-κB stimulation.
  • Utilizing monoclonal antibodies and mutant TNF proteins.

Main Results:

  • Conserved regions in TNF are primarily associated with cell death induction, not NF-κB stimulation.
  • Specific peptides induced apoptosis (P12, P13, P1213) or necrosis (P14, P15, P16, P1516) independently of TNF receptor binding.
  • P16 induced necrosis via cell membrane disruption; P1213 induced apoptosis through TRADD and complex II formation.
  • A conserved linear sequence within P1213 was identified as the determinant for TNF-induced apoptosis.

Conclusions:

  • TNF's primitive function of inducing apoptosis is governed by a specific conserved linear sequence.
  • This sequence, identified within the P1213 peptide, is critical for initiating TNF-driven apoptosis.
  • The study elucidates the molecular basis of TNF's role in programmed cell death.