PMID- 37516734
OWN - NLM
STAT- MEDLINE
DCOM- 20230801
LR  - 20230803
IS  - 2041-4889 (Electronic)
VI  - 14
IP  - 7
DP  - 2023 Jul 29
TI  - The deubiquitinating enzyme OTUD7b protects dendritic cells from TNF-induced 
      apoptosis by stabilizing the E3 ligase TRAF2.
PG  - 480
LID - 10.1038/s41419-023-06014-5 [doi]
LID - 480
AB  - 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-kappaB 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.
CI  - (c) 2023. The Author(s).
FAU - Harit, Kunjan
AU  - Harit K
AD  - Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical 
      School, 30625, Hannover, Germany.
FAU - Bhattacharjee, Rituparna
AU  - Bhattacharjee R
AD  - Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical 
      School, 30625, Hannover, Germany.
FAU - Matuschewski, Kai
AU  - Matuschewski K
AUID- ORCID: 0000-0001-6147-8591
AD  - Department of Molecular Parasitology, Institute of Biology, Humboldt University, 
      10115, Berlin, Germany.
FAU - Becker, Jennifer
AU  - Becker J
AD  - Institute for Experimental Infection Research, TWINCORE, Centre for Experimental 
      and Clinical Infection Research, a joint venture between the Helmholtz Centre for 
      Infection Research and the Hannover Medical School, Hannover, Germany.
FAU - Kalinke, Ulrich
AU  - Kalinke U
AUID- ORCID: 0000-0003-0503-9564
AD  - Institute for Experimental Infection Research, TWINCORE, Centre for Experimental 
      and Clinical Infection Research, a joint venture between the Helmholtz Centre for 
      Infection Research and the Hannover Medical School, Hannover, Germany.
FAU - Schluter, Dirk
AU  - Schluter D
AD  - Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical 
      School, 30625, Hannover, Germany.
FAU - Nishanth, Gopala
AU  - Nishanth G
AUID- ORCID: 0000-0002-7280-5663
AD  - Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical 
      School, 30625, Hannover, Germany. Gopalakrishna.Nishanth@mh-hannover.de.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230729
PL  - England
TA  - Cell Death Dis
JT  - Cell death & disease
JID - 101524092
RN  - EC 3.4.19.12 (Deubiquitinating Enzymes)
RN  - 0 (TNF Receptor-Associated Factor 2)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 2.3.2.27 (Ubiquitin-Protein Ligases)
RN  - 0 (Ubiquitins)
RN  - 0 (TRAF2 protein, mouse)
RN  - 0 (PSMD2 protein, human)
RN  - EC 3.4.- (OTUD7B protein, human)
RN  - EC 3.4.19.12 (Otud7b protein, mouse)
SB  - IM
MH  - Animals
MH  - Humans
MH  - Mice
MH  - Apoptosis
MH  - *CD8-Positive T-Lymphocytes
MH  - Dendritic Cells
MH  - Deubiquitinating Enzymes
MH  - TNF Receptor-Associated Factor 2
MH  - Tumor Necrosis Factor-alpha/pharmacology
MH  - *Ubiquitin-Protein Ligases
MH  - Ubiquitins
PMC - PMC10387084
COIS- The authors declare no competing interests.
EDAT- 2023/07/30 01:06
MHDA- 2023/07/31 11:42
PMCR- 2023/07/29
CRDT- 2023/07/29 23:16
PHST- 2023/05/19 00:00 [received]
PHST- 2023/07/19 00:00 [accepted]
PHST- 2023/05/19 00:00 [revised]
PHST- 2023/07/31 11:42 [medline]
PHST- 2023/07/30 01:06 [pubmed]
PHST- 2023/07/29 23:16 [entrez]
PHST- 2023/07/29 00:00 [pmc-release]
AID - 10.1038/s41419-023-06014-5 [pii]
AID - 6014 [pii]
AID - 10.1038/s41419-023-06014-5 [doi]
PST - epublish
SO  - Cell Death Dis. 2023 Jul 29;14(7):480. doi: 10.1038/s41419-023-06014-5.