Recent BCR stimulation induces a negative autoregulatory loop via FBXO10 mediated degradation of HGAL

Fengjie Guo, Yuan Luo, Xiaoyu Jiang, Xiao Qing Lu, Domenico Roberti, Chen Lossos, Kranthi Kunkalla, Marco Magistri, Lixin Rui, Ramiro Verdun, Francisco Vega, Vincent T. Moy, Izidore S. Lossos

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
JournalLeukemia
DOIs
StateAccepted/In press - Jan 1 2019
Externally publishedYes

Fingerprint

Germinal Center
Lymphoma
B-Lymphocytes
Phosphorylation
Immunoreceptor Tyrosine-Based Inhibition Motif
SKP Cullin F-Box Protein Ligases
Cell Membrane
Lipoylation
B-Lymphocyte Subsets
Calcium-Sensing Receptors
Ubiquitination
Proteolysis
Amino Acids
Mutation

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Recent BCR stimulation induces a negative autoregulatory loop via FBXO10 mediated degradation of HGAL. / Guo, Fengjie; Luo, Yuan; Jiang, Xiaoyu; Lu, Xiao Qing; Roberti, Domenico; Lossos, Chen; Kunkalla, Kranthi; Magistri, Marco; Rui, Lixin; Verdun, Ramiro; Vega, Francisco; Moy, Vincent T.; Lossos, Izidore S.

In: Leukemia, 01.01.2019.

Research output: Contribution to journalArticle

Guo, Fengjie ; Luo, Yuan ; Jiang, Xiaoyu ; Lu, Xiao Qing ; Roberti, Domenico ; Lossos, Chen ; Kunkalla, Kranthi ; Magistri, Marco ; Rui, Lixin ; Verdun, Ramiro ; Vega, Francisco ; Moy, Vincent T. ; Lossos, Izidore S. / Recent BCR stimulation induces a negative autoregulatory loop via FBXO10 mediated degradation of HGAL. In: Leukemia. 2019.
@article{24becb5a90714037a2f92e256c900996,
title = "Recent BCR stimulation induces a negative autoregulatory loop via FBXO10 mediated degradation of HGAL",
abstract = "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.",
author = "Fengjie Guo and Yuan Luo and Xiaoyu Jiang and Lu, {Xiao Qing} and Domenico Roberti and Chen Lossos and Kranthi Kunkalla and Marco Magistri and Lixin Rui and Ramiro Verdun and Francisco Vega and Moy, {Vincent T.} and Lossos, {Izidore S.}",
year = "2019",
month = "1",
day = "1",
doi = "10.1038/s41375-019-0579-5",
language = "English (US)",
journal = "Leukemia",
issn = "0887-6924",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Recent BCR stimulation induces a negative autoregulatory loop via FBXO10 mediated degradation of HGAL

AU - Guo, Fengjie

AU - Luo, Yuan

AU - Jiang, Xiaoyu

AU - Lu, Xiao Qing

AU - Roberti, Domenico

AU - Lossos, Chen

AU - Kunkalla, Kranthi

AU - Magistri, Marco

AU - Rui, Lixin

AU - Verdun, Ramiro

AU - Vega, Francisco

AU - Moy, Vincent T.

AU - Lossos, Izidore S.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85074335658&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85074335658&partnerID=8YFLogxK

U2 - 10.1038/s41375-019-0579-5

DO - 10.1038/s41375-019-0579-5

M3 - Article

C2 - 31570756

AN - SCOPUS:85074335658

JO - Leukemia

JF - Leukemia

SN - 0887-6924

ER -