Early lethality, functional NF-kappaB activation, and increased sensitivity to TNF-induced cell death in

W C Yeh1, A Shahinian, D Speiser

  • 1Amgen Institute, Department of Medical Biophysics, University of Toronto, Ontario, Canada.

Immunity
|December 9, 1997
PubMed

Insights

Tumor necrosis factor receptor-associated factor 2 (TRAF2) is crucial for immune cell survival. TRAF2 deficiency leads to premature death and heightened sensitivity to TNF-induced apoptosis, highlighting its protective role.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • Tumor necrosis factor (TNF) signaling is critical for immune responses and homeostasis.
  • TRAF2 (TNF receptor-associated factor 2) is an intracellular protein involved in TNF receptor signaling.
  • The precise physiological role of TRAF2 in vivo remains incompletely understood.

Purpose of the Study:

  • To elucidate the physiological function of TRAF2.
  • To investigate the consequences of TRAF2 deficiency in a living organism.

Main Methods:

  • Generation and analysis of TRAF2-deficient (traf2-/-) mice.
  • Assessment of survival, physical development, and lymphoid organ cellularity.
  • Evaluation of TNF-induced apoptosis in hematopoietic progenitor cells.
  • Analysis of JNK/SAPK and NF-kappaB signaling pathway activation in TRAF2-deficient cells.

Main Results:

  • TRAF2-deficient mice exhibited normal birth weight but developed progressive runting and premature death.
  • Significant atrophy of the thymus and spleen, along with depletion of B cell precursors, was observed.
  • TRAF2-deficient thymocytes and hematopoietic progenitors showed increased sensitivity to TNF-induced cell death.
  • Elevated serum TNF levels were detected in TRAF2-deficient animals.
  • A severe reduction in TNF-mediated JNK/SAPK activation, but only a mild effect on NF-kappaB activation, was noted in traf2-/- cells.

Conclusions:

  • TRAF2 plays an essential role in maintaining immune homeostasis and preventing excessive TNF-induced apoptosis.
  • TRAF2 is required for a critical TNF-induced signaling pathway that protects against cell death, independent of NF-kappaB activation.
  • Evidence suggests the existence of TRAF2-independent pathways for NF-kappaB activation.

Related Concept Videos

Enzyme-linked Receptors01:00

Enzyme-linked Receptors

Enzyme-linked receptors are proteins that act as both receptor and enzyme, activating multiple intracellular signals. This is a large group of receptors that include the receptor tyrosine kinase (RTK) family. Many growth factors and hormones bind to and activate the RTKs.
Neurotrophin (NT) receptors are a family of RTKs, including trkA, trkB, and trkC (tropomyosin-related kinase) receptors. TrkA is specific for nerve growth factor (NGF), neurotrophin-6, and neurotrophin-7. TrkB binds...
NF-κB-dependent Signaling Pathway02:26

NF-κB-dependent Signaling Pathway

The transcription factor NF-κB was discovered in 1986 in the lab of Nobel laureate Professor David Baltimore, for its interaction with the immunoglobulin light chain enhancer in B-cells. After more than three decades of study, it is now evident that NF-κB regulates the expression of over 100 genes. Most of these genes play an essential role in the innate and adaptive immune responses as well as the inflammatory responses of animals.
NF-κB-dependent Signaling Mechanism
The heterodimer of NF-κB...
The Extrinsic Apoptotic Pathway01:17

The Extrinsic Apoptotic Pathway

The extrinsic apoptotic pathway is initiated when extracellular death-inducing signals, such as specific cytokines, activate the death receptors expressed on the cell surface. The immune cells involved in this pathway are natural killer cells (NK cells) and cytotoxic T-lymphocytes. NK cells are critical in innate immune response, while cytotoxic T-lymphocytes are associated with adaptive immune response. These cells recognize specific receptors expressed on the altered cells and activate...