Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UNIPROT:P62988 (
Ubiquitin
)
4,326
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Regulated protein degradation contributes to plant development by mediating signaling events in many hormone, light, and developmental pathways.
Ubiquitin
ligases recognize and ubiquitinate target proteins for subsequent degradation by the 26S proteasome. The multisubunit SCF is the best-studied class of ubiquitin ligases in Arabidopsis (Arabidopsis thaliana). However, the extent of SCF participation in signaling networks is unclear. SCFs are composed of four subunits:
CULLIN 1
(
CUL1
), ASK, RBX1, and an F-box protein. Null mutations in
CUL1
are embryo lethal, limiting insight into the role of
CUL1
and SCFs in later stages of development. Here, we describe a viable and fertile weak allele of
CUL1
, called cul1-6. cul1-6 plants have defects in seedling and adult morphology. In addition to reduced auxin sensitivity, cul1-6 seedlings are hyposensitive to ethylene, red, and blue light conditions. An analysis of protein interactions with the cul1-6 gene product suggests that both RUB (related to ubiquitin) modification and interaction with the SCF regulatory protein CAND1 (cullin associated and neddylation dissociated) are disrupted. These findings suggest that the morphological defects observed in cul1-6 plants are caused by defective SCF complex formation. Characterization of weak cul1 mutants provides insight into the role of SCFs throughout plant growth and development.
...
PMID:A new CULLIN 1 mutant has altered responses to hormones and light in Arabidopsis. 1715 85
TRAIL-R2 (DR5) is a clinically-relevant therapeutic target and a key target for immune effector cells. Herein, we identify a novel interaction between TRAIL-R2 and the Skp1-
Cullin-1
-F-box (SCF) Cullin-Ring E3
Ubiquitin
Ligase complex containing Skp2 (SCF
Skp2
). We find that SCF
Skp2
can interact with both TRAIL-R2's pre-ligand association complex (PLAC) and ligand-activated death-inducing signalling complex (DISC). Moreover,
Cullin-1
interacts with TRAIL-R2 in its active NEDDylated form. Inhibiting
Cullin-1
's DISC recruitment using the NEDDylation inhibitor MLN4924 (Pevonedistat) or siRNA increased apoptosis induction in response to TRAIL. This correlated with enhanced levels of the caspase-8 regulator FLIP at the TRAIL-R2 DISC, particularly the long splice form, FLIP(L). We subsequently found that FLIP(L) (but not FLIP(S), caspase-8, nor the other core DISC component FADD) interacts with
Cullin-1
and Skp2. Importantly, this interaction is enhanced when FLIP(L) is in its DISC-associated, C-terminally truncated p43-form. Prevention of FLIP(L) processing to its p43-form stabilises the protein, suggesting that by enhancing its interaction with SCF
Skp2
, cleavage to the p43-form is a critical step in FLIP(L) turnover. In support of this, we found that silencing any of the components of the SCF
Skp2
complex inhibits FLIP ubiquitination, while overexpressing
Cullin-1
/Skp2 enhances its ubiquitination in a NEDDylation-dependent manner. DISC recruitment of TRAF2, previously identified as an E3 ligase for caspase-8 at the DISC, was also enhanced when
Cullin-1
's recruitment was inhibited, although its interaction with
Cullin-1
was found to be mediated indirectly via FLIP(L). Notably, the interaction of p43-FLIP(L) with
Cullin-1
disrupts its ability to interact with FADD, caspase-8 and TRAF2. Collectively, our results suggest that processing of FLIP(L) to p43-FLIP(L) at the TRAIL-R2 DISC enhances its interaction with co-localised SCF
Skp2
, leading to disruption of p43-FLIP(L)'s interactions with other DISC components and promoting its ubiquitination and degradation, thereby modulating TRAIL-R2-mediated apoptosis.
...
PMID:The SCF
Skp2
ubiquitin ligase complex modulates TRAIL-R2-induced apoptosis by regulating FLIP(L). 3231 99
