Erythroid mitochondrial retention triggers myeloid-dependent type I interferon in human SLE.
Emerging evidence supports that mitochondrial dysfunction contributes to systemic lupus erythematosus (SLE) pathogenesis. Here we show that programmed mitochondrial removal, a hallmark of mammalian erythropoiesis, is defective in SLE. Specifically, we demonstrate that during human erythroid cell maturation, a hypoxia-inducible factor (HIF)-mediated metabolic switch is responsible for the activation of the ubiquitin-proteasome system (UPS), which precedes and is necessary for the autophagic removal of mitochondria. A defect in this pathway leads to accumulation of red blood cells (RBCs) carrying mitochondria (Mito+ RBCs) in SLE patients and in correlation with disease activity. Antibody-mediated internalization of Mito+ RBCs induces type I interferon (IFN) production through activation of cGAS in macrophages. Accordingly, SLE patients carrying both Mito+ RBCs and opsonizing antibodies display the highest levels of blood IFN-stimulated gene (ISG) signatures, a distinctive feature of SLE.
Pubmed ID: 34384544 RIS Download
Research resources used in this publication
- MaxQuant (RRID:SCR_014485) (software resource)
- Image Lab Software (RRID:SCR_014210) (software resource)
- Biorender (RRID:SCR_018361) (web application)
- Proteome Discoverer (RRID:SCR_014477) (software resource)
- DESeq2 (RRID:SCR_015687) (software resource)
- htseq-count (RRID:SCR_011867) (software resource)
- SAMTOOLS (RRID:SCR_002105) (software resource)
- cutadapt (RRID:SCR_011841) (software resource)
- HISAT2 (RRID:SCR_015530) (software resource)
- FastQC (RRID:SCR_014583) (software resource)
- Fiji (RRID:SCR_002285) (software resource)
- GraphPad Prism (RRID:SCR_002798) (software resource)
- FlowJo (RRID:SCR_008520) (software resource)
Additional research tools detected in this publication
None foundAntibodies used in this publication
- Ultra-LEAF(TM) Purified anti-human CD64 (RRID:AB_2810455)
- Anti-L-lactyllysine rabbit pAb (RRID:AB_2868521)
- Anti-Ubiquitin (linkage-specific K48) antibody (RRID:AB_2783797)
- PGC-1alpha (3G6) Rabbit mAb (RRID:AB_823600)
- Anti-Nrf2 antibody (RRID:AB_2687540)
- PSMA7 antibody (RRID:AB_10680295)
- Rabbit Anti-Proteasome 19S S1 Polyclonal Antibody, Unconjugated (RRID:AB_2237798)
- PSMC5 antibody (RRID:AB_303705)
- Proteasome 20S alpha 1+2+3+5+6+7 antibody [MCP231] (RRID:AB_2171376)
- 20S Proteasome beta1 (D-9) (RRID:AB_10988741)
- IRF-3 (D83B9) Rabbit mAb (RRID:AB_1904036)
- STING Antibody (RRID:AB_11178391)
- cGAS (D1D3G) Rabbit mAb (RRID:AB_2732795)
- Anti-GAPDH antibody [EPR16891] (RRID:AB_2630358)
- IFIT1 antibody (RRID:AB_1310334)
- MX1 antibody (RRID:AB_10677452)
- Rabbit Anti-LDHA Monoclonal Antibody, Unconjugated, Clone C4B5 (RRID:AB_2066887)
- Rabbit Anti-Hexokinase II Monoclonal Antibody, Unconjugated, Clone C64G5 (RRID:AB_2232946)
- PKM1/2 (C103A3) Rabbit mAb (RRID:AB_2163695)
- Mouse Anti-15-LO Monoclonal Antibody, Unconjugated (RRID:AB_2137289)
- Recombinant Anti-SDHA antibody [EPR9043(B)] (RRID:AB_2884996)
- Recombinant Anti-ATP5A antibody [EPR13030(B)] (RRID:AB_2801536)
- Hemoglobin subunit alpha antibody [EPR3608] (RRID:AB_10561594)
- Mouse Anti-Actin, beta Monoclonal Antibody, Unconjugated, Clone mAbcam 8226 (RRID:AB_306371)
- Rabbit Anti-MnSOD Polyclonal Antibody, Unconjugated (RRID:AB_300434)
- Recombinant Anti-Hsp60 antibody [EPR18245-93] (RRID:AB_2814692)
- Recombinant Alexa Fluor® 488 Anti-TOMM40 antibody [EPR6932(2)] (RRID:AB_2889325)
- Peroxiredoxin 3 antibody [EPR8114] (RRID:AB_11150432)
- Cytochrome C antibody [7H8.2C12] (RRID:AB_300470)
- RPL29 Polyclonal Antibody (RRID:AB_2545021)
- Rabbit Anti-LC3B Polyclonal Antibody, Unconjugated (RRID:AB_881429)
- LAMP1 antibody (RRID:AB_2134489)
- ATP5A antibody [7H10BD4F9] (RRID:AB_10858175)
- Band 3 antibody [EPR1426] (RRID:AB_10862297)
- Anti-COX IV antibody [mAbcam33985] - Mitochondrial Marker (RRID:AB_879754)
- Goat Anti-Human Isg15 / ucrp Polyclonal antibody, Unconjugated (RRID:AB_2249121)
- BNIP3 antibody [EPR4034] (RRID:AB_10864714)
- HIF-2 alpha Antibody (RRID:AB_10000872)
- APC/Cyanine7 anti-human CD235a (Glycophorin A) (RRID:AB_2650978)
- PE/Cyanine7 anti-human CD71 (RRID:AB_2563119)
- FITC anti-human CD36 (RRID:AB_1575025)
- MAb to Human Interferon-Alpha/Beta R2 (IFNAR2) (CD118), neutralizing, Clone MMHAR-2 (RRID:AB_387828)
- Human Red Blood Cell RBC Antibody (RRID:AB_220010)
- CD233-PE (RRID:AB_2656482)
- APC anti-human CD49d (RRID:AB_2130041)
Associated grants
- Agency: NIAMS NIH HHS, United States
Id: P50 AR070594 - Agency: NIAID NIH HHS, United States
Id: U19 AI082715 - Agency: NIAID NIH HHS, United States
Id: U19 AI144301
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This is a list of tools and resources that we have found mentioned in this publication.
Ultra-LEAF(TM) Purified anti-human CD64 (antibody)
RRID:AB_2810455
This monoclonal targets CD64
View all literature mentionsAnti-L-lactyllysine rabbit pAb (antibody)
RRID:AB_2868521
This polyclonal targets lactyllysine
View all literature mentionsAnti-Ubiquitin (linkage-specific K48) antibody (antibody)
RRID:AB_2783797
This monoclonal targets Ubiquitin
View all literature mentionsPGC-1alpha (3G6) Rabbit mAb (antibody)
RRID:AB_823600
This monoclonal targets PGC-1alpha (3G6) Rabbit mAb
View all literature mentionsAnti-Nrf2 antibody (antibody)
RRID:AB_2687540
This polyclonal targets Nrf2
View all literature mentionsPSMA7 antibody (antibody)
RRID:AB_10680295
This polyclonal targets PSMA7 antibody
View all literature mentionsRabbit Anti-Proteasome 19S S1 Polyclonal Antibody, Unconjugated (antibody)
RRID:AB_2237798
This polyclonal targets Rpn2
View all literature mentionsProteasome 20S alpha 1+2+3+5+6+7 antibody [MCP231] (antibody)
RRID:AB_2171376
This monoclonal targets PSMA1
View all literature mentions20S Proteasome beta1 (D-9) (antibody)
RRID:AB_10988741
This monoclonal targets 20S Proteasome beta1 (D-9)
View all literature mentionsIRF-3 (D83B9) Rabbit mAb (antibody)
RRID:AB_1904036
This monoclonal targets IRF-3
View all literature mentionsSTING Antibody (antibody)
RRID:AB_11178391
This polyclonal targets STING
View all literature mentionscGAS (D1D3G) Rabbit mAb (antibody)
RRID:AB_2732795
This monoclonal targets cGAS
View all literature mentionsAnti-GAPDH antibody [EPR16891] (antibody)
RRID:AB_2630358
This monoclonal targets
View all literature mentionsIFIT1 antibody (antibody)
RRID:AB_1310334
This polyclonal targets IFIT1 antibody
View all literature mentionsMX1 antibody (antibody)
RRID:AB_10677452
This polyclonal targets MX1 antibody
View all literature mentionsRabbit Anti-LDHA Monoclonal Antibody, Unconjugated, Clone C4B5 (antibody)
RRID:AB_2066887
This monoclonal targets LDHA
View all literature mentionsRabbit Anti-Hexokinase II Monoclonal Antibody, Unconjugated, Clone C64G5 (antibody)
RRID:AB_2232946
This monoclonal targets Hexokinase II
View all literature mentionsPKM1/2 (C103A3) Rabbit mAb (antibody)
RRID:AB_2163695
This monoclonal targets Pkm2
View all literature mentionsMouse Anti-15-LO Monoclonal Antibody, Unconjugated (antibody)
RRID:AB_2137289
This monoclonal targets LRRC23
View all literature mentionsRecombinant Anti-SDHA antibody [EPR9043(B)] (antibody)
RRID:AB_2884996
This recombinant monoclonal targets Flavoprotein (FP) subunit of succinate dehydrogenase
View all literature mentionsRecombinant Anti-ATP5A antibody [EPR13030(B)] (antibody)
RRID:AB_2801536
This recombinant targets ATP5A
View all literature mentionsHemoglobin subunit alpha antibody [EPR3608] (antibody)
RRID:AB_10561594
This monoclonal targets Hemoglobin subunit alpha antibody [EPR3608]
View all literature mentionsMouse Anti-Actin, beta Monoclonal Antibody, Unconjugated, Clone mAbcam 8226 (antibody)
RRID:AB_306371
This monoclonal targets beta Actin
View all literature mentionsRabbit Anti-MnSOD Polyclonal Antibody, Unconjugated (antibody)
RRID:AB_300434
This polyclonal targets Superoxide Dismutase 2
View all literature mentionsRecombinant Anti-Hsp60 antibody [EPR18245-93] (antibody)
RRID:AB_2814692
This monoclonal targets Hsp60
View all literature mentionsRecombinant Alexa Fluor® 488 Anti-TOMM40 antibody [EPR6932(2)] (antibody)
RRID:AB_2889325
This recombinant monoclonal targets TOMM40
View all literature mentionsPeroxiredoxin 3 antibody [EPR8114] (antibody)
RRID:AB_11150432
This monoclonal targets Peroxiredoxin 3 antibody [EPR8114]
View all literature mentionsCytochrome C antibody [7H8.2C12] (antibody)
RRID:AB_300470
This monoclonal targets Cytochrome C antibody [7H8.2C12]
View all literature mentionsRPL29 Polyclonal Antibody (antibody)
RRID:AB_2545021
This unknown targets RPL29
View all literature mentionsRabbit Anti-LC3B Polyclonal Antibody, Unconjugated (antibody)
RRID:AB_881429
This polyclonal targets LC3B
View all literature mentionsLAMP1 antibody (antibody)
RRID:AB_2134489
This polyclonal targets Lamp1
View all literature mentionsATP5A antibody [7H10BD4F9] (antibody)
RRID:AB_10858175
This monoclonal targets ATP5A antibody [7H10BD4F9]
View all literature mentionsBand 3 antibody [EPR1426] (antibody)
RRID:AB_10862297
This monoclonal targets Band 3 antibody [EPR1426]
View all literature mentionsAnti-COX IV antibody [mAbcam33985] - Mitochondrial Marker (antibody)
RRID:AB_879754
This monoclonal targets COX IV
View all literature mentionsGoat Anti-Human Isg15 / ucrp Polyclonal antibody, Unconjugated (antibody)
RRID:AB_2249121
This polyclonal targets Human ISG15 / UCRP
View all literature mentionsBNIP3 antibody [EPR4034] (antibody)
RRID:AB_10864714
This monoclonal targets BNIP3 antibody [EPR4034]
View all literature mentionsHIF-2 alpha Antibody (antibody)
RRID:AB_10000872
This unknown targets HIF-2 alpha
View all literature mentionsAPC/Cyanine7 anti-human CD235a (Glycophorin A) (antibody)
RRID:AB_2650978
This monoclonal targets CD235a
View all literature mentionsPE/Cyanine7 anti-human CD71 (antibody)
RRID:AB_2563119
This monoclonal targets CD71
View all literature mentionsFITC anti-human CD36 (antibody)
RRID:AB_1575025
This monoclonal targets CD36
View all literature mentionsMAb to Human Interferon-Alpha/Beta R2 (IFNAR2) (CD118), neutralizing, Clone MMHAR-2 (antibody)
RRID:AB_387828
This monoclonal targets MAb to Human Interferon-Alpha/Beta R2 (IFNAR2) (CD118) neutralizing Clone MMHAR-2
View all literature mentionsHuman Red Blood Cell RBC Antibody (antibody)
RRID:AB_220010
This polyclonal targets Human Red Blood Cell RBC
View all literature mentionsAPC anti-human CD49d (antibody)
RRID:AB_2130041
This monoclonal targets CD49d
View all literature mentionsMaxQuant (software resource)
RRID:SCR_014485
A quantitative proteomics software package for analyzing large-scale mass-spectrometric data sets. It is a set of algorithms that include peak detection and scoring of peptides, mass calibration, database searches for protein identification, protein quantification, and provides summary statistics.
View all literature mentionsImage Lab Software (software resource)
RRID:SCR_014210
Imaging software used to acquire and analyze images from specific Bio-Rad imaging systems. Users can analyze gel or blot features, capture optimized image data, and generate a report of the data. Image Lab software exclusively runs on the Gel Doc EZ imager, Gel Doc XR+ imaging system, ChemiDo MP, ChemiDoc XRS+ imaging systems, Criterion Stain Free imager, and the GS-900calibrated densitometer.
View all literature mentionsBiorender (web application)
RRID:SCR_018361
Web tool for graphical illustrations for biological systems by BioRender. Used for articles and presentations. Collection of pre made icons and templates from life science fields for scientific illustrations. Customized icons possible on request.
View all literature mentionsProteome Discoverer (software resource)
RRID:SCR_014477
Software for identifying, characterizing, and quantifying proteins in biological samples. Can be used for range of proteomics workflows such as protein and peptide identification, PTM analysis, and isobaric mass tagging for quantification. Supports multiple database search algorithms and multiple dissociation techniques.
View all literature mentionsDESeq2 (software resource)
RRID:SCR_015687
Software package for differential gene expression analysis based on the negative binomial distribution. Used for analyzing RNA-seq data for differential analysis of count data, using shrinkage estimation for dispersions and fold changes to improve stability and interpretability of estimates.
View all literature mentionshtseq-count (software resource)
RRID:SCR_011867
Script distributed with the HT-Seq Python framework for processing RNA-seq or DNA-seq data.
View all literature mentionsSAMTOOLS (software resource)
RRID:SCR_002105
Original SAMTOOLS package has been split into three separate repositories including Samtools, BCFtools and HTSlib. Samtools for manipulating next generation sequencing data used for reading, writing, editing, indexing,viewing nucleotide alignments in SAM,BAM,CRAM format. BCFtools used for reading, writing BCF2,VCF, gVCF files and calling, filtering, summarising SNP and short indel sequence variants. HTSlib used for reading, writing high throughput sequencing data.
View all literature mentionscutadapt (software resource)
RRID:SCR_011841
Software tool that removes adapter sequences from DNA sequencing reads.
View all literature mentionsHISAT2 (software resource)
RRID:SCR_015530
Graph-based alignment of next generation sequencing reads to a population of genomes.
View all literature mentionsFastQC (software resource)
RRID:SCR_014583
Quality control software that perform checks on raw sequence data coming from high throughput sequencing pipelines. This software also provides a modular set of analyses which can give a quick impression of the quality of the data prior to further analysis.
View all literature mentionsFiji (software resource)
RRID:SCR_002285
Software package as distribution of ImageJ and ImageJ2 together with Java, Java3D and plugins organized into coherent menu structure. Used to assist research in life sciences.
View all literature mentionsGraphPad Prism (software resource)
RRID:SCR_002798
Statistical analysis software that combines scientific graphing, comprehensive curve fitting (nonlinear regression), understandable statistics, and data organization. Designed for biological research applications in pharmacology, physiology, and other biological fields for data analysis, hypothesis testing, and modeling.
View all literature mentionsFlowJo (software resource)
RRID:SCR_008520
Software for single-cell flow cytometry analysis. Its functions include management, display, manipulation, analysis and publication of the data stream produced by flow and mass cytometers.
View all literature mentions
