Identifiers
NAME:RBCK1:RNF31:SHARPIN
Maps_Modules
HMC:AVOIDING_IMMUNE_DESTRUCTION
Innate Immunity / IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS
References
PMID:24699077
LUBAC, linear ubiquitin chain assembly complex comprises????SHANK-associated RH-domain interactor (SHARPIN), heme-oxidized IRP2 ubiquitin ligase 1 homolog (HOIL1/RBCK1) and the E3 HOIL-1???interacting protein (HOIP/RNF31)
???is recruited to the TNFR1 complex via binding to the autoubiquitinated c-IAP1 and c-IAP2 proteins to mediate the assembly of linear polyubiquitin chains on NF-??B essential modifier (NEMO/IKBKG) and RIPK1
PMID:21232017, PMID:21133840, PMID:17301840
cIAP1 and cIAP2 modify RIP1, TRAF2 and
themselves with K63-linked ubiquitin chains. This creates docking sites for the LUBAC complex, an E3 ligase capable of forming linear polyubiquitin chains. The LUBAC complex ubiquitinates NEMO, a subunit of the IKK complex, which by help of its IKK2 subunit also interacts
with TRADD-bound TRAF2. In parallel, the TAK1-TAB 2 complex interacts with K63-ubiquitin modi???ed RIP1 by use of the K63-ubiquitin binding TAB 2 subunit. TAK1 become activated and then phosphorylates and activates IKK2 which in turn now phosphorylates IjBa, marking it
for K48-ubiquitination and proteasomal degradation.
PMID:24958845
NFkB activation (IkBa degradation) downstream of TNF is LUBAC-dependent.
in_re884( Innate Immunity ):
PMID:14660645, PMID:18264787, PMID:11460167
Activated TAK1 phosphorylates IKK-beta proteins
leading to activation of NF-??B downstream of HMGB1.
PMID:24958845, PMID:24699077
The LUBAC complex ubiquitinates NEMO, a subunit of the IKK complex downstream of TNF and upregulates IkBa degradetion.
PMID:11280761
VEGF signaling blocs TNF-?? induced activation of I??B kinase (IKK complex).This decreased IKK activation correlated with the inhibition of I??B?? phosphorylation and degradation of I??B?? and I??B?? in HPCs, and this inhibition is inhdependent or FLT1 and KDR