TRAF7 potentiates MEKK3-induced AP1 and CHOP activation and induces apoptosis

Liang-Guo Xu1, Lian-Yun Li, Hong-Bing Shu

  • 1Integrated Department of Immunology, National Jewish Medical and Research Center, University of Colorado Health Sciences Center, Denver, Colorado 80206, USA.

Insights

Researchers identified TRAF7, a novel tumor necrosis factor receptor-associated factor (TRAF). TRAF7 interacts with MEKK3, influencing AP1 and CHOP activation and inducing apoptosis.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Immunology

Background:

  • Tumor necrosis factor receptor-associated factor (TRAF) proteins are key mediators in signaling pathways.
  • TRAF family members regulate NF-kappaB, JNK, and p38 activation downstream of TNF and TIR receptors.
  • Most TRAF proteins possess a functional N-terminal RING finger domain.

Purpose of the Study:

  • To identify and characterize novel members of the TRAF protein family.
  • To investigate the role of a newly identified TRAF protein, TRAF7, in cellular signaling pathways.
  • To elucidate the functional domains of TRAF7 involved in MEKK3 signaling and apoptosis induction.

Main Methods:

  • Protein identification and domain analysis.
  • Co-immunoprecipitation assays to study protein interactions.
  • Antisense RNA technology for gene silencing.
  • Overexpression studies and domain mapping for functional analysis.

Main Results:

  • A novel TRAF protein, TRAF7, was identified, featuring a RING finger, zinc finger, and seven WD40 repeats.
  • TRAF7 specifically interacts with MEKK3, enhancing MEKK3-mediated AP1 and CHOP activation.
  • TRAF7 depletion via antisense RNA abrogated MEKK3-induced AP1 and CHOP activation.
  • Overexpression of TRAF7 triggered caspase-dependent apoptosis, with distinct domains mediating signaling and apoptosis.

Conclusions:

  • TRAF7 is a novel member of the TRAF family, playing a significant role in MEKK3 signaling.
  • TRAF7 is implicated in the regulation of AP1 and CHOP activation.
  • TRAF7 contributes to the induction of apoptosis through specific functional domains.

Related Concept Videos

MAPK Signaling Cascades01:07

MAPK Signaling Cascades

Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
The Intrinsic Apoptotic Pathway01:31

The Intrinsic Apoptotic Pathway

Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
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...
Interactions Between Signaling Pathways01:19

Interactions Between Signaling Pathways

Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a rapamycin-insensitive companion...
Apoptosis01:30

Apoptosis

Apoptosis is a combination of two Greek words, 'apo' and 'ptosis,' meaning separation and falling off, respectively. Hippocrates used this word to describe gangrene, which was caused due to bandaging of fractured bones. Apoptosis was distinguished from necrosis in 1970 when John Kerr reported observations of morphological changes occurring during apoptosis. During one experiment, he observed that the disruption of blood supply to the liver tissue resulted in a size reduction of the tissue.