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Zhang Lingqiang's team and He Fuchu's team from the Institute of Biomics, Academy of Military Medicine, Academy of Military Sciences, together with Wei Wenyi's team from Harvard Medical School and Liu Cuihua's team from the Institute of Microbiology, Chinese Academy of Sciences, published an article in Molecular Cell recently, analyzing the regulation of blood vessels by linear ubiquitination New mechanism generated
Ubiquitination controls protein degradation and signal transduction through the combination of ubiquitin chains and substrates, and ultimately affects every cell process
The linear ubiquitin chain assembly complex (LUBAC) is composed of the ubiquitin ligase HOIP and two regulatory subunits HOIL-1L and SHARPIN, and is responsible for the formation of linear ubiquitin chains on substrates such as NEMO, RIPK1, and RIPK2
ALK1 is a substrate modified by linear ubiquitination
In order to determine the physiological function of the linear ubiquitin chain in embryonic development, the researchers first generated Otulin-deficient mice
When studying the underlying mechanism, they found that the C-terminal phosphorylation of Smad1/5 in Otulin-KO embryos decreased at E12.
Linear ubiquitination of ALK1 reduces downstream Smad1/5 signaling
The researchers found that HOIP inhibitor 11a limits the formation of linear ubiquitin chains on ALK1
If this is the case, does OTULIN deubiquitinate ALK1 to promote Smad1/5 activation? They found that, as expected, OTULIN cleaved the linear ubiquitin chain on ALK1 catalyzed by LUBAC
Next, in order to confirm that ALK1 is the true physiological target of linear ubiquitination and is responsible for the death of Otulin-null embryos, the researchers plan to compensate the signal intensity of ALK1-Smad1/5 in Otulin-null embryos to save the phenotype of Otulin-null embryos
HOIP inhibitors can rescue the abnormal phenotype of patient-derived EC
Previous studies have shown that mutations in ALK1 can cause type 2 hereditary hemorrhagic telangiectasia (HHT2), which is an autosomal dominant vascular disease in which patients have obvious symptoms in multiple locations due to arteriovenous malformations Vascular disease
They screened 25 families of HHT patients with ALK1 mutations and found that a pair of mothers and children carried ALK1 G309S mutations
In general, the author has confirmed the synergistic effect of OTULIN and LUBAC through a series of experiments to balance the angiogenesis of endothelial cells by specifically editing the linear ubiquitination of ALK1
Original Search
Fu et al.