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The deubiquitinating enzyme OTUD7b protects dendritic cells from TNF-induced apoptosis by stabilizing the E3 ligase

Kunjan Harit1, Rituparna Bhattacharjee1, Kai Matuschewski2

  • 1Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, 30625, Hannover, Germany.

Cell Death & Disease
|July 29, 2023
PubMed

Insights

Ovarian tumor deubiquitinating enzyme 7b (OTUD7b) prevents dendritic cell (DC) death induced by tumor necrosis factor (TNF), enhancing CD8+ T cell responses. This discovery offers new targets for manipulating immune cell survival.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • Tumor necrosis factor (TNF) signaling in dendritic cells (DCs) involves complex cell death and inflammatory pathways regulated by ubiquitination.
  • The precise molecular mechanisms determining DC fate downstream of TNF receptor activation remain incompletely understood.

Purpose of the Study:

  • To investigate the role of ovarian tumor deubiquitinating enzyme 7b (OTUD7b) in regulating TNF-induced cell death in dendritic cells.
  • To elucidate the molecular mechanisms by which OTUD7b influences DC survival and immune responses.

Main Methods:

  • Utilized human and murine dendritic cells.
  • Investigated the interaction between OTUD7b, TRAF2, and RIPK1.
  • Analyzed ubiquitination status (K48 and K63 linkages) and protein stability.
  • Assessed NF-κB and MAP kinase activation, cytokine production (IL-12), and expression of anti-apoptotic proteins (cFLIP, Bcl-xL).
  • Employed a murine model of experimental cerebral malaria to study DC-specific OTUD7b-deficient mice.

Main Results:

  • OTUD7b inhibits TNF-induced apoptosis in DCs, promoting survival.
  • OTUD7b stabilizes TRAF2 by preventing its K48-ubiquitination and proteasomal degradation.
  • TRAF2-mediated K63-ubiquitination of RIPK1 activates NF-κB and MAP kinases, leading to IL-12 production and expression of cFLIP and Bcl-xL.
  • DC-specific OTUD7b deficiency in mice resulted in DC apoptosis and impaired CD8+ T cell-mediated immunity in a malaria model.

Conclusions:

  • OTUD7b acts as a crucial molecular switch controlling DC survival downstream of TNF signaling.
  • Targeting OTUD7b and its regulation of the ubiquitin network offers a strategy to modulate DC responses and immune cell priming.

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