2016 tietoa
(Tämän LUBAC- kompleksin löysin kun luin RBR- ryhmän E3 ubikitinaaseista HOIL-1 ja HOIP. niillä on muitkin nimiä. RBR tarkoittaa että niillä on rakenteessa RING-IBR-RING
( RING between RING-rakenne)
Toisilta nimiltä ne ovat
HOIL1 on RBCK1, RNF54, ZRAN , UBCE71P3 ( HOIP ligandi) HOIL1 on
HOIP on RNF31 (ring finger protein), ZIBRA, PAUL.
SHARPIN taas tuli vastaan muussa yhteydessä . Sen UBL- domeeni sitoutuu HOIP UBA- domeeniin ja aktivoi sen).
(Lymfosyytin antigeenireseptorivälitteisessä aktivaatiossa toimii myös signalosomi CARM1 = CARD11, BCL10, MALT1 (CBM-kompleksi), joka aktivoi NFKB transkriptiofaktorin rekrytoimalla LUBAC ja laskee valloilleen MALT1 parakaspaasiaktiivisuuden) .
Jos HOIL1-jäsen puuttuu LUBAC on inhibitiossa.
MALT-1 aktivoi lymfosyytti-, muovaa NFkV signaalia , vaikuttqaa myös lymfoomien kasvuun.
HOIL1 on nimeltään myös UbeM4 (UBC7IP3) deubikitinaasin kanssa interaktiota tekevä proteiini).
(Muuten- minulla ei vielä ole käsitystä miten tämä ja tavllinen RLR, NLR, TLR3 signalointikartta tähän LUBC- CBM- TLR3 signalointiin suhtautuu).
Abstract
The linear ubiquitin chain assembly complex (LUBAC),
consisting of
SHANK-associated RH-domain-interacting protein (SHARPIN),
heme-oxidized IRP2 ubiquitin ligase-1 (HOIL-1),
and HOIL-1-interacting protein (HOIP),
is a critical regulator of inflammation and immunity.
This is highlighted by the fact that patients with perturbed linear ubiquitination caused by mutations in the Hoip or Hoil-1 genes, resulting in knockouts of these proteins, may simultaneously suffer from immunodeficiency and autoinflammation. TLR3 plays a crucial, albeit controversial, role in viral infection and tissue damage. We identify a pivotal role of LUBAC in TLR3 signaling and discover a functional interaction between LUBAC components and TLR3 as crucial for immunity to influenza A virus infection. On the biochemical level, we identify LUBAC components as interacting with the TLR3-signaling complex (SC), thereby enabling TLR3-mediated gene activation. Absence of LUBAC components increases formation of a previously unrecognized TLR3-induced death-inducing SC, leading to enhanced cell death. Intriguingly, excessive TLR3-mediated cell death, induced by double-stranded RNA present in the skin of SHARPIN-deficient chronic proliferative dermatitis mice (cpdm), is a major contributor to their autoinflammatory skin phenotype, as genetic coablation of Tlr3 substantially ameliorated cpdm dermatitis. Thus, LUBAC components control TLR3-mediated innate immunity, thereby preventing development of immunodeficiency and autoinflammation.
SHANK-associated RH-domain-interacting protein (SHARPIN),
heme-oxidized IRP2 ubiquitin ligase-1 (HOIL-1),
and HOIL-1-interacting protein (HOIP),
is a critical regulator of inflammation and immunity.
This is highlighted by the fact that patients with perturbed linear ubiquitination caused by mutations in the Hoip or Hoil-1 genes, resulting in knockouts of these proteins, may simultaneously suffer from immunodeficiency and autoinflammation. TLR3 plays a crucial, albeit controversial, role in viral infection and tissue damage. We identify a pivotal role of LUBAC in TLR3 signaling and discover a functional interaction between LUBAC components and TLR3 as crucial for immunity to influenza A virus infection. On the biochemical level, we identify LUBAC components as interacting with the TLR3-signaling complex (SC), thereby enabling TLR3-mediated gene activation. Absence of LUBAC components increases formation of a previously unrecognized TLR3-induced death-inducing SC, leading to enhanced cell death. Intriguingly, excessive TLR3-mediated cell death, induced by double-stranded RNA present in the skin of SHARPIN-deficient chronic proliferative dermatitis mice (cpdm), is a major contributor to their autoinflammatory skin phenotype, as genetic coablation of Tlr3 substantially ameliorated cpdm dermatitis. Thus, LUBAC components control TLR3-mediated innate immunity, thereby preventing development of immunodeficiency and autoinflammation.
- PMID:
- 27810922
- PMCID:
- PMC5110014
- DOI:
- 10.1084/jem.20160041
- [Indexed for MEDLINE]
Netistä löytyy myös uusi artikkeli heinäkuulta 2018 ja siihen liittyy kuvia, joissa selvitetään miten antigeeni jouduttuaan imusolun -solun reseptoriin ( TCR ja BCR) sitten antaa signaloinnin CBM -signalosomiin ja NFkB ja JNK aktivoituvat ja siinä vaiheessa paralleelisti signalosomi vapauttaa proteaasiaktiivisuuden, dissosioituu ja LUBAC ja siihen assosioituneet - tekijät hajoavat.
Tekijät Regnase-1 ja Roquin: Muistiin.
https://www.ncbi.nlm.nih.gov/pubmed/29127149https://www.ncbi.nlm.nih.gov/pubmed/29127149
