Prion-like Aggregation of Mitochondrial Antiviral Signaling Protein in Lupus Patients Is Associated With Increased Levels of Type I Interferon.
Increased levels of type I interferon (IFN) and type I IFN-regulated genes are found in patients with systemic lupus erythematosus (SLE) and may be central to its pathogenesis. Mitochondrial antiviral signaling protein (MAVS) is a key regulator of type I IFN that undergoes a dramatic prion-like aggregation and self propagates the activation signal from viral RNA to amplify downstream IFN production. We undertook this study to determine whether such MAVS aggregates might play a role in the sustained increased production of type I IFN in SLE.



Peripheral blood mononuclear cells were isolated and mitochondrial extracts were prepared. MAVS aggregation was detected by semidenatured agarose gel electrophoresis and confirmed by immunofluorescence staining. MAVS-associated signaling proteins were analyzed by Western blotting. MAVS aggregation-associated gene expression signature was analyzed by microarray.



In blood cells from 22 of 67 SLE patients, essentially all MAVS was in a high molecular weight aggregated form. None of 6 rheumatoid arthritis patients and only 3 of 33 healthy controls had abnormal MAVS. Compared to MAVS aggregate-negative patients, MAVS aggregate-positive SLE patients had significantly higher serum levels of IFNβ and significantly increased levels of autoantibodies against Sm and U1 RNP. Gene array data revealed a characteristic gene expression pattern in these patients, with altered expression of genes involved in IFN signaling and membrane trafficking.



Persistent MAVS aggregates may lead to increased type I IFN production and result in unmitigated signals leading to autoimmunity.
Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania. wshao@temple.edu.
Wen-Hai
WH
Shao
Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania.
Daniel H
DH
Shu
Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania.
Yuxuan
Y
Zhen
Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania.
Brendan
0000-0002-4689-6821
B
Hilliard
Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania.
Stephen O
SO
Priest
Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania.
Matteo
M
Cesaroni
University of North Carolina at Chapel Hill.
Jenny P-Y
JP
Ting
Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania. philco@temple.edu.
Philip L
PL
Cohen
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000328:Adult; D000974:Antibodies, Antinuclear / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism; D001323:Autoantibodies / Q000276:immunology; D015153:Blotting, Western; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D007370:Interferon Type I / Q000276:immunology / Q000378:metabolism*; D016899:Interferon-beta / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000235:genetics; D066263:Protein Aggregation, Pathological / Q000276:immunology / Q000378:metabolism*; D011951:Receptors, Complement / Q000235:genetics; D017412:Ribonucleoprotein, U1 Small Nuclear / Q000276:immunology; D046888:Tissue Array Analysis; D059467:Transcriptome; D044767:Ubiquitin-Protein Ligases / Q000235:genetics; D055517:snRNP Core Proteins / Q000276:immunology
D048868:Adaptor Proteins, Signal Transducing; D000974:Antibodies, Antinuclear; D001323:Autoantibodies; D036341:Intercellular Signaling Peptides and Proteins; D007370:Interferon Type I; C505371:MAVS protein, human; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C503285:NLRC3 protein, human; C527006:NLRX1 protein, human; D011951:Receptors, Complement; D017412:Ribonucleoprotein, U1 Small Nuclear; C032402:complement 1q receptor; D055517:snRNP Core Proteins; D016899:Interferon-beta; C515578:MARCHF5 protein, human; D044767:Ubiquitin-Protein Ligases