TRAF molecules in cell signaling and in human diseases

Xie, Ping

doi:10.1186/1750-2187-8-7

Journal of Molecular Signaling

Table 6 In vivo functions of TRAFs in mice

From: TRAF molecules in cell signaling and in human diseases

Genotype	Type of knockout	Phenotype	References
TRAF1
TRAF1−/−	Germline	Viable and normal lymphocyte development	[173]
		Skin hypersensitive to TNF-induced necrosis	[173]
		Hyperproliferation in response to T cell receptor signaling	[173]
		Enhanced Th2 responses	[266]
		Lack of 4-1BB-mediated survival responses in CD8 and memory T cells	[78, 79, 171]
		Required for 4-1BB-induced NF-κB1 activation in T cells	[31]
		Constitutive NF-κB2 activation in CD8 T cells	[31]
TRAF2
TRAF2−/−	Germline	Progressively runted and die within 3 weeks after birth	[267]
		Atrophy of the thymus and spleen; depletion of B cell precursors	[267]
		Elevated serum TNF levels; cells sensitive to TNF-induced apoptosis	[267]
		Severe reduction in TNF-mediated JNK activation	[267]
		Severe colitis; drastic changes in the colonic microbiota	[261]
		Increased number of Th17 cells in the colonic lamina propria	[261]
		Apoptosis of colonic epithelial cells due to TNFR1 signaling	[261]
		IL-10-secreting neutrophils accumulated in peripheral blood and bone marrow	[262]
TRAF2flox/flox, CD19-Cre	B cell-specific	Prolonged B cell survival independent of BAFF	[36]
		Splenomegaly and lymphadenopathy	[36]
		Constitutive NF-κB2 activation in B cells	[36]
		Slower and decreased CD40-induced phosphorylation of JNK, p38 and ERK	[74]
		Reduced germinal center formation following SRBC immunization	[74]
TRAF2flox/flox, Lck-Cre	T cell-specific	Normal T cell survival; constitutive NF-κB2 activation in T cells	[36]
TRAF2flox/flox, Albumin-Cre	Hepatocyte-specific	Severely impaired hyperglycemic response to glucagon	[268]
TRAF3
TRAF3−/−	Germline	Progressively runted; die by 10 days after birth	[269]
		Impaired T cell responses	[269]
TRAF3flox/flox, CD19-Cre	B cell-specific	Prolonged B cell survival independent of BAFF	[36, 270]
		Splenomegaly and lymphadenopathy	[36, 270]
		Autoimmune manifestations and hyperimmunoglobulinemia	[270]
		Increased T-independent antibody responses	[270]
		Development of B1 lymphomas and splenic marginal zone lymphomas	[271]
		Enhanced signaling by TLR3, TLR4, TLR7, and TLR9 in B cells	[272]
		Accelerated CD40-induced phosphorylation of JNK, p38 and ERK	[74]
TRAF3flox/flox, Lck-Cre	T cell-specific	Normal T cell survival; constitutive NF-kB2 activation in T cells	[36]
TRAF3flox/flox, CD4-Cre	T cell-specific	Normal T cell survival; constitutive NF-kB2 activation in T cells	[11]
		Normal CD4 and CD8 T cell development; increased number of Treg cells	[11]
		Defective T-dependent antibody responses	[11]
		Impaired T cell-mediated immunity to bacterial infection	[11]
		Defective T cell responses to co-stimulation by T cell receptor and CD28	[11]
TRAF4
TRAF4−/−	Germline	Embryonic lethal but with great individual variation	[258, 259]
		Respiratory disorder and wheezing caused by tracheal ring disruption	[258, 259]
		Surviving mutant mice manifest numerous developmental abnormalities	[258, 259]
		Altered locomotion coordination typical of ataxia	[258, 259]
		High incidence of spina bifida	[258, 259]
		Degeneration of a high number of Purkinje cells	[260]
		Increased rates of pulmonary inflammation	[260]
		Reduced migration of DCs; normal development of T and B lymphocytes	[273]
		Inhibits IL-17 signaling and Th17-mediated autoimmune encephalomyelitis	[164]
TRAF5
TRAF5−/−	Germline	Viable and normal development	[274]
		Mild defect in T-dependent antibody responses	[274]
		Defective in Th1/Th2 differentiation	[275]
TRAF6
TRAF6−/−	Germline	Perinatal and postnatal lethality	[264, 265]
		Severe osteopetrosis; defective in osteoclast formation	[264, 265]
		Defective IL-1, CD40 and LPS signaling in lymphocytes	[264, 265]
		Defective in lymph node organogenesis	[265]
		Reduced number of immature B cells in the bone marrow	[265]
		Severe defect in the Treg development in thymus	[276]
		Defective development, maturation and activation of DCs	[277]
		Impaired cytokine production in mast cells following FcεRI aggregation	[278]
		Hypohidrotic ectodermal dysplasia	[279]
TRAF6flox/flox, CD19-Cre	B cell-specific	Reduced number of mature B cells in the bone marrow and spleen	[280]
		Impaired T-dependent and T-independent antibody responses	[280]
		Lack of CD5+ B-1 cells	[280]
TRAF6flox/flox, CD4-Cre	T cell-specific	Multiorgan inflammatory disease; hyperactivation of the PI3K-Akt pathway	[281]
		Resistant to suppression by CD4+CD25+ regulatory T cells	[281]
		Resistant to anergizing signals	[282]
		A profound defect in generating CD8 memory T cells;	[283]
		Defective AMPK activation and mitochondrial fatty acid oxidation	[283]
		Specific increase in Th17 differentiation	[284]
		More sensitive to TGFβ-induced Smad2/3 activation and proliferation arrest	[284]
		A severe defect in the Treg development	[276]
TRAF6flox/flox, MCK-Cre	Skeletal muscle-specific	Improved muscle preservation in response to starvation or cancer cachexia	[60, 285, 286]
		Improved regeneration of myofibers upon injury	[60, 285, 286]
		Augmented the M2 macrophage phenotype in injured muscle tissues	[60, 285, 286]
		Upregulated Notch signaling and reduced inflammatory cytokine production	[287, 288]

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