The deubiquitinating enzyme OTUD7b protects dendritic cells from TNF-induced apoptosis by stabilizing the E3 ligase TRAF2

Abstract

The cytokine tumor necrosis factor (TNF) critically regulates the intertwined cell death and pro-inflammatory signaling pathways of dendritic cells (DCs) via ubiquitin modification of central effector molecules, but the intrinsic molecular switches deciding on either pathway are incompletely defined. Here, we uncover that the ovarian tumor deubiquitinating enzyme 7b (OTUD7b) prevents TNF-induced apoptosis of DCs in infection, resulting in efficient priming of pathogen-specific CD8+ T cells. Mechanistically, OTUD7b stabilizes the E3 ligase TNF-receptor-associated factor 2 (TRAF2) in human and murine DCs by counteracting its K48-ubiquitination and proteasomal degradation. TRAF2 in turn facilitates K63-linked polyubiquitination of RIPK1, which mediates activation of NF-κB and MAP kinases, IL-12 production, and expression of anti-apoptotic cFLIP and Bcl-xL. We show that mice with DC-specific OTUD7b-deficiency displayed DC apoptosis and a failure to induce CD8+ T cell-mediated brain pathology, experimental cerebral malaria, in a murine malaria infection model. Together, our data identify the deubiquitinating enzyme OTUD7b as a central molecular switch deciding on survival of human and murine DCs and provides a rationale to manipulate DC responses by targeting their ubiquitin network downstream of the TNF receptor pathway.

OTU deubiquitinase 7B facilitates the hyperthermia‐induced inhibition of lung cancer progression through enhancing Smac‐mediated mitochondrial dysfunction

“…OTUD7B increases levels of complex/ring body (APC/C) substrates by binding, deubiquitinating, and stabilizing, leading to dysregulation of the mitotic process 16 . Harit et al 39 suggest that OTUD7B links the ubiquitination level of K48 and k63, thereby facilitating the interaction between GβL and SIN1 to promote mTORC2 formation in response to multiple growth signals. In contrast to the high expression of OTUD7B in other cancers, 40,41 we found that loss of OTUD7B was associated with lung cancer metastasis and verified its involvement in hyperthermia‐induced cancer cell suppression.…”