PMID- 24244017
OWN - NLM
STAT- MEDLINE
DCOM- 20140218
LR  - 20211203
IS  - 1550-6606 (Electronic)
IS  - 0022-1767 (Print)
IS  - 0022-1767 (Linking)
VI  - 191
IP  - 12
DP  - 2013 Dec 15
TI  - Optineurin insufficiency impairs IRF3 but not NF-kappaB activation in immune cells.
PG  - 6231-40
LID - 10.4049/jimmunol.1301696 [doi]
AB  - Optineurin is a widely expressed polyubiquitin-binding protein that has been 
      implicated in regulating cell signaling via its NF-kappaB essential 
      modulator-homologous C-terminal ubiquitin (Ub)-binding region. Its functions are 
      controversial, with in vitro studies finding that optineurin suppressed 
      TNF-mediated NF-kappaB activation and virus-induced activation of IFN regulatory 
      factor 3 (IRF3), whereas bone marrow-derived macrophages (BMDMs) from mice 
      carrying an optineurin Ub-binding point mutation had normal TLR-mediated NF-kappaB 
      activation and diminished IRF3 activation. We have generated a mouse model in 
      which the entire Ub-binding C-terminal region is deleted (Optn(470T)). Akin to 
      C-terminal optineurin mutations found in patients with certain neurodegenerative 
      diseases, Optn(470T) was expressed at substantially lower levels than the native 
      protein, allowing assessment not only of the lack of Ub binding, but also of 
      protein insufficiency. Embryonic lethality with incomplete penetrance was 
      observed for 129 x C57BL/6 Optn(470T/470T) mice, but after further backcrossing 
      to C57BL/6, offspring viability was restored. Moreover, the mice that survived 
      were indistinguishable from wild type littermates and had normal immune cell 
      distributions. Activation of NF-kappaB in Optn(470T) BMDM and BM-derived dendritic 
      cells with TNF or via TLR4, T cells via the TCR, and B cells with LPS or 
      anti-CD40 was normal. In contrast, optineurin and/or its Ub-binding function was 
      necessary for optimal TANK binding kinase 1 and IRF3 activation, and both 
      Optn(470T) BMDMs and bone marrow-derived dendritic cells had diminished IFN-beta 
      production upon LPS stimulation. Importantly, Optn(470T) mice produced less IFN-beta 
      upon LPS challenge. Therefore, endogenous optineurin is dispensable for NF-kappaB 
      activation but necessary for optimal IRF3 activation in immune cells.
FAU - Munitic, Ivana
AU  - Munitic I
AD  - Laboratory of Immune Cell Biology, National Cancer Institute, National Institutes 
      of Health, Bethesda, MD 20892.
FAU - Giardino Torchia, Maria Letizia
AU  - Giardino Torchia ML
FAU - Meena, Netra Pal
AU  - Meena NP
FAU - Zhu, Guozhi
AU  - Zhu G
FAU - Li, Caiyi C
AU  - Li CC
FAU - Ashwell, Jonathan D
AU  - Ashwell JD
LA  - eng
GR  - Z01 BC010779-01/Intramural NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Intramural
DEP - 20131115
PL  - United States
TA  - J Immunol
JT  - Journal of immunology (Baltimore, Md. : 1950)
JID - 2985117R
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (Eye Proteins)
RN  - 0 (Interferon Regulatory Factor-3)
RN  - 0 (Irf3 protein, mouse)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Membrane Transport Proteins)
RN  - 0 (NF-kappa B)
RN  - 0 (Optn protein, mouse)
RN  - 0 (Receptors, Antigen, B-Cell)
RN  - 0 (Tlr4 protein, mouse)
RN  - 0 (Toll-Like Receptor 4)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 77238-31-4 (Interferon-beta)
RN  - EC 2.7.1.- (Tbk1 protein, mouse)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Cell Cycle Proteins
MH  - Chimera
MH  - Crosses, Genetic
MH  - Dendritic Cells/immunology
MH  - Eye Proteins/genetics/*physiology
MH  - Gene Expression Regulation/immunology
MH  - Genes, Lethal
MH  - HEK293 Cells
MH  - Humans
MH  - Immunity, Innate
MH  - Interferon Regulatory Factor-3/*metabolism
MH  - Interferon-beta/biosynthesis/genetics
MH  - Lipopolysaccharides/pharmacology
MH  - Lymphocyte Subsets/immunology/*metabolism
MH  - Macrophages/immunology/*metabolism
MH  - Male
MH  - Membrane Transport Proteins
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - NF-kappa B/*metabolism
MH  - Phosphorylation
MH  - Protein Processing, Post-Translational
MH  - Protein Serine-Threonine Kinases/metabolism
MH  - Protein Structure, Tertiary
MH  - Receptors, Antigen, B-Cell/immunology
MH  - Sequence Deletion
MH  - Signal Transduction
MH  - Toll-Like Receptor 4/immunology
MH  - Tumor Necrosis Factor-alpha/pharmacology
MH  - Ubiquitination
PMC - PMC3886234
MID - NIHMS531757
EDAT- 2013/11/19 06:00
MHDA- 2014/02/19 06:00
PMCR- 2014/12/15
CRDT- 2013/11/19 06:00
PHST- 2013/11/19 06:00 [entrez]
PHST- 2013/11/19 06:00 [pubmed]
PHST- 2014/02/19 06:00 [medline]
PHST- 2014/12/15 00:00 [pmc-release]
AID - jimmunol.1301696 [pii]
AID - 10.4049/jimmunol.1301696 [doi]
PST - ppublish
SO  - J Immunol. 2013 Dec 15;191(12):6231-40. doi: 10.4049/jimmunol.1301696. Epub 2013 
      Nov 15.