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SCF(Fbw7) modulates the NFkB signaling pathway by targeting NFkB2 for ubiquitination and destruction

Hidefumi Fukushima1, Akinobu Matsumoto, Hiroyuki Inuzuka

  • 1Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.

Cell Reports
|June 19, 2012
PubMed

Insights

The F-box protein 7 (Fbw7) E3 ligase controls NFkB2/p100 stability via ubiquitination and destruction. This regulation impacts NFkB signaling, cell death sensitivity, and T cell differentiation, suggesting Fbw7

Area of Science:

  • Molecular Biology
  • Cellular Signaling
  • Immunology

Background:

  • NFkB/Rel proteins are crucial for cellular processes, requiring tight physiological control.
  • NFkB2/p100 acts as a suppressor of NFkB, but its degradation mechanism is unclear.
  • SCF(Fbw7) is a ubiquitin ligase complex implicated in protein degradation.

Purpose of the Study:

  • To elucidate the molecular mechanism regulating NFkB2/p100 degradation.
  • To investigate the role of SCF(Fbw7) in controlling NFkB2/p100 stability.
  • To determine the physiological consequences of Fbw7-mediated regulation of NFkB signaling.

Main Methods:

  • Utilized Fbw7 knockout (Fbw7-/-) cells to study NFkB2/p100 levels.
  • Employed GSK3 inhibition to assess its role in NFkB2 ubiquitination and destruction.
  • Introduced wild-type and mutant Fbw7 to rescue NFkB activity.
  • Depleted Fbw7 in T cells to examine effects on NFkB signaling and differentiation.

Main Results:

  • NFkB2/p100 ubiquitination and destruction are regulated by SCF(Fbw7) in a GSK3-dependent manner.
  • Fbw7 deficiency leads to increased NFkB2/p100, reduced NFkB signaling, and heightened sensitivity to TNFa-induced cell death.
  • Reintroduction of wild-type Fbw7 restores NFkB activity, while mutants do not.
  • T cell-specific Fbw7 depletion reduces NFkB activity and impairs T cell differentiation.

Conclusions:

  • Fbw7 is identified as the physiological E3 ligase governing NFkB2/p100 stability.
  • Fbw7's regulation of NFkB activity may contribute to its tumor-suppressor function.
  • Dysregulation of Fbw7 impacts NFkB signaling and T cell homeostasis.

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