Background: TNF receptor-associated factor 2 (TRAF2) is a key adaptor molecule in the TNF receptor (TNFR) signaling pathway.
Results: TRAF-interacting protein (TRIP) inhibits Lys63 -linked TRAF2 ubiquitination by blocking the binding of the cofactor sphingosine 1-phosphate (S1P) to the TRAF2 RING domain. Conclusion: TRIP negatively regulates the TRAF2 ubiquitin-dependent pathway by modulating the TRAF2-S1P interaction. Significance: TRIP is an important cellular regulator of the TNFR-mediated inflammatory response.
Lateral meningocele syndrome (LMS) is a rare genetic disorder characterized by neurological complications and osteoporosis. LMS is associated with mutations in exon 33 of NOTCH3 leading to a truncated protein lacking sequences for NOTCH3 degradation and presumably causing NOTCH3 gain-of-function. To create a mouse model reproducing human LMS-associated mutations, we utilized CRISPR/Cas9 to introduce a tandem termination codon at bases 6691-6696 (ACCAAG>TAATGA) and verified this mutation (Notch3 tm1.1Ecan
Individuals with Hajdu-Cheney syndrome (HCS) present with osteoporosis, and HCS is associated with mutations causing deletions of the proline-, glutamic acid-, serine-, and threonine-rich (PEST) domain that are predicted to enhance NOTCH2 stability and cause gain-of-function. Previously, we demonstrated that mice harboring mutations analogous to those in HCS () are severely osteopenic because of enhanced bone resorption. We attributed this phenotype to osteoclastic sensitization to the receptor activator of nuclear factor-κB ligand and increased osteoblastic tumor necrosis factor superfamily member 11 () expression. Here, to determine the individual contributions of osteoclasts and osteoblasts to HCS osteopenia, we created a conditional-by-inversion ( ) model in which Cre recombination generates a allele expressing a Notch2 mutant lacking the PEST domain. Germ line inversion phenocopied the mutant, validating the model. To activate Notch2 in osteoclasts or osteoblasts, mice were bred with mice expressing Cre from the or the promoter, respectively. These crosses created experimental mice harboring a allele in Cre-expressing cells and control littermates expressing a wild-type transcript. inversion in-expressing cells had no skeletal consequences and did not affect the capacity of bone marrow macrophages to form osteoclasts In contrast, inversion in osteoblasts led to generalized osteopenia associated with enhanced bone resorption in the cancellous bone compartment and with suppressed endocortical mineral apposition rate. Accordingly, activation in osteoblast-enriched cultures from mice induced expression. In conclusion, introduction of the HCS mutation in osteoblasts, but not in osteoclasts, causes osteopenia.
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