Beta-arrestin 2 is required for complement C1q expression in macrophages and constrains factor-independent survival.
The beta-arrestins (ARRB1 and ARRB2) regulate G-protein coupled receptor (GPCR) dependent- and independent-signaling pathways and are ubiquitously expressed. Here we show that ARRB2 mRNA and protein expression is enriched in macrophages, and that it regulates complement C1q expression and cell survival. Basal and Toll-like receptor (TLR) inducible expression of mRNAs encoding the complement subcomponents C1qa, C1qb and C1qc was greatly reduced in bone marrow-derived macrophages (BMM) from ARRB2-deficient, but not ARRB1-deficient mice, while factor-independent survival of ARRB2(-/-) BMM was enhanced compared to wildtype BMM. TatARRB2(23), a cell-permeable peptide that contains the MAPK JNK-binding motif from within the ARRB2 C-domain, impaired ARRB2 interaction with JNK3, down-regulated C1q expression and permitted factor-independent survival in BMM, thus suggesting that this peptide antagonises ARRB2 function in macrophages. In addition, TatARRB2(23) transiently activated the phosphorylation of JNK and ERK, but not p38 in BMM. These data imply that ARRB2 acts to limit JNK/ERK activation and survival in macrophages, but is required for basal and TLR-inducible complement C1q expression. Given that loss of C1q function is strongly associated with the development of systemic lupus erythematosus, ARRB2 may act to limit the development of autoimmune disease.
Lattin
Jane E
JE
The University of Queensland, Institute for Molecular Bioscience, QLD 4072, Australia.
Greenwood
Kathryn P
KP
Daly
Norelle L
NL
Kelly
Gregory
G
Zidar
David A
DA
Clark
Richard J
RJ
Thomas
Walter G
WG
Kellie
Stuart
S
Craik
David J
DJ
Hume
David A
DA
Sweet
Matthew J
MJ
D000595:Amino Acid Sequence; D000818:Animals; D019390:Arrestins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001854:Bone Marrow Cells / Q000166:cytology; D002460:Cell Line; D002470:Cell Survival; D015922:Complement C1q / Q000276:immunology / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor; D008264:Macrophages / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry; D010641:Phenotype; D000071559:beta-Arrestin 1; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
C000605253:ARRB1 protein, human; C000605254:ARRB2 protein, human; C000605255:Arrb1 protein, mouse; C000605258:Arrb2 protein, mouse; D019390:Arrestins; D010455:Peptides; D000071559:beta-Arrestin 1; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D015922:Complement C1q; D016173:Macrophage Colony-Stimulating Factor