Recent BCR stimulation induces a negative autoregulatory loop via FBXO10 mediated degradation of HGAL.
B-Lymphocytes
/ metabolism
Cell Membrane
/ metabolism
F-Box Proteins
/ metabolism
Germinal Center
/ metabolism
Humans
Intracellular Signaling Peptides and Proteins
/ metabolism
Lymphoma, Large B-Cell, Diffuse
/ metabolism
Microfilament Proteins
/ metabolism
Neoplasm Proteins
/ metabolism
Phosphorylation
/ physiology
Receptors, Antigen, B-Cell
/ metabolism
Signal Transduction
/ physiology
Ubiquitin-Protein Ligases
/ metabolism
Journal
Leukemia
ISSN: 1476-5551
Titre abrégé: Leukemia
Pays: England
ID NLM: 8704895
Informations de publication
Date de publication:
02 2020
02 2020
Historique:
received:
25
03
2019
accepted:
17
09
2019
revised:
11
09
2019
pubmed:
2
10
2019
medline:
5
8
2020
entrez:
2
10
2019
Statut:
ppublish
Résumé
Regulating B-cell receptor (BCR) signaling after antigenic stimulation is essential to properly control immune responses. Currently known mechanisms of inhibiting BCR signaling are via co-receptor stimulation and downstream immunoreceptor tyrosine-based inhibition motif (ITIM) phosphorylation. Herein we demonstrate that BCR stimulation induces rapid and reversible palmitoylation of the SCF-FBXO10 ubiquitin E3 ligase. This results in FBXO10 relocation to the cell membrane, where it targets the human germinal center-associated lymphoma (HGAL) protein for ubiquitylation and degradation, leading to decreases in both BCR-induced calcium influx and phosphorylation of proximal BCR effectors. Importantly, FBXO10 recognition and degradation of HGAL is phosphorylation independent and instead relies on a single evolutionarily conserved HGAL amino acid residue (H91) and FBXO10 relocalization to the cytoplasmic membrane. Together our findings demonstrate the first evidence of negative BCR signaling regulation from direct BCR stimulation and define the temporospatial functions of the FBXO10-HGAL axis. FBXO10 is infrequently mutated in DLBCL but some of these mutations deregulate BCR signaling. These observations may have important implications on lymphomagenesis and other immune processes.
Identifiants
pubmed: 31570756
doi: 10.1038/s41375-019-0579-5
pii: 10.1038/s41375-019-0579-5
doi:
Substances chimiques
F-Box Proteins
0
FBXO10 protein, human
0
GCSAM protein, human
0
Intracellular Signaling Peptides and Proteins
0
Microfilament Proteins
0
Neoplasm Proteins
0
Receptors, Antigen, B-Cell
0
Ubiquitin-Protein Ligases
EC 2.3.2.27
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
553-566Références
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