mutations appeared in about one percent of the ALS patients--a large proportion in the context of a complex disease with multiple genetic components, according to Goldstein.
Indeed, dysregulations in common molecular players, including TARDBP [3, 4], FUS [5, 6], UBQLN2 , VCP , TBK1
[9-11], CHMP2B [12, 13], and expanded hexanucleotide repeats within the C9ORF72 gene [14, 15], contribute to both diseases, indicating that these ALS-FTD-linked genes can cause dysfunctions in both the motor system and cognition.
Among these, one of the striking observations is the differential expression of numerous ALS-linked genes (i.e., ANG, DCTN1, SQSTM1, and TBK1
) involved in autophagy, a highly conserved and tightly regulated cellular self-degradative process whose alteration leads to an impaired clearance of toxic protein aggregates and/or of damaged mitochondria that represent some of the best characterized hallmarks of both SALS and FALS .
Activation of TRAF3 activates TBK1
and IKKe, which phosphorylate and activate the transcription factor IRF3 that stimulates the transcription of anti-inflammatory cytokines.
MAVS and TRIF then trigger signaling cascades leading to the activation of different cytosolic kinases (I[kappa]B kinases (IKK) and TANK-binding kinase 1 (TBK1
)), which in turn induce activation of the key transcription factors NF-[kappa]B and IRF3 [79, 80].
To further investigate whether the MyD88-independent signaling pathway was involved in CPS modulation of MO-induced proinflammatory responses in sheep epithelial cells, several key components of MyD88-independent signaling cascade, including TRAF3, TBK1
, TRIF, and TRAM, were evaluated at both of transcriptional level (Figure 4(a)) and translational level (Figures 4(b) and 4(c)).
The importance of interferons was highlighted in our previous results on the TLR4 signaling pathway, where TLR4, TICAM1, TICAM2, TBK1
, IRF3, IFNA1, and IFNA2 mRNAs showed changes in the murine lupus-like models .
This ligand engages in a distinct signaling pathway that involves cytoplasmic nucleic sensor STING, downstream kinase TBK1
, and interferon regulatory factor (IRF) 3/7 .
tuberculosis-derived MDP via NOD2 and downstream activation of RIP2, TBK1
, and IRF5 .
Several reports have shown that stimulator of interferon genes (STING), interferon regulatory factor 3 (IRF3), and TANK-binding kinase 1 (TBK1
), which are molecules associated with the signal pathway activated by host DNA, is required for the adjuvant activity of aluminum particle [74, 75].
Activation of TRAF3 by TRIF is important to generate a link between TRIF and TANK-binding kinase 1 (TBK1
, also known as NF-[kappa]B activating kinase, NAK), and this in turn activates TBK1
Antibodies against TLR4 (96kDa), MyD88 (33kDa), p65 (65kDa), pERK (4244kDa), TBK1
(80kDa), IRF3 (50kDa), protein C-reactive (PCR) (30kDa), and TNF[alpha] (27kDa) were purchased from Santa Cruz Biotechnology (Santa Cruz, CA); antibodies against CD14 (40 kDa), TRAF6 (55 kDa), TRIF (66 kDa), and IKKi/IKKe (80 kDa) were purchased from Abcam (Cambridge, UK); and antibodies against pIKK (85-87 kDa), pI[kappa]B (40 kDa), p38 (43 kDa), pP38 (43 kDa), and pIRF3 (45-55 kDa) were purchased from Cell Signaling Technology (Beverly, MA).