The GAR/RGG motif defines a family of nuclear alarmins

Abstract

The nucleus is the target of autoantibodies in many diseases, which suggests intrinsic nuclear adjuvants that confer its high autoimmunogenicity. Nucleolin (NCL) is one abundant nucleolar autoantigen in systemic lupus erythematosus (SLE) patients and, in lupus-prone mice, it elicits autoantibodies early. With purified NCL, we observed that it was a potent alarmin that activated monocytes, macrophages and dendritic cells and it was a ligand for TLR2 and TLR4. NCL released by necrotic cells also exhibited alarmin activity. The NCL alarmin activity resides in its glycine/arginine-rich (GAR/RGG) motif and can be displayed by synthetic GAR/RGG peptides. Two more GAR/RGG-containing nucleolar proteins, fibrillarin (FBRL) and GAR1, were also confirmed to be novel alarmins. Therefore, the GAR/RGG alarmin motif predicts a family of nucleolar alarmins. The apparent prevalence of nucleolar alarmins suggests their positive contribution to tissue homeostasis by inducing self-limiting tissue inflammation with autoimmunity only occurring when surveillance is broken down.

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“…Nucleolin is a multifunctional protein which highly expressed in lymphocytes, monocytes, and neutrophils in dogs with malignant neoplasia (22). purified NCL can activate monocytes and macrophages (23). But there are few studies on the effect of PTN-NCL on male spermatogenesis.…”

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“…During this process, SMN interacts with snoRNP proteins as ribonucleoprotein complex subunit 1 (GAR1) and Fibrillarin ( 47 ). Those are members of the alarmin protein family which activate Toll-like receptors on the cells surface of antigen presenting cells (APC) such as macrophages ( 48 ). Activation of macrophages results in regulation of several snoRNAs ( 49 ).…”

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“…Like microorganisms, apoptotic cells are also targeted by C1q albeit that C1q binds to apoptotic cells directly without antibodies ( 8 ). C1q binds predominantly to the exposed nucleolus ( 9 ), which causes C1r/C1s activation and proteolytic degradation of nucleolar autoantigens and alarmins ( 10 – 12 ). Wu et al.…”

“…the chromatin network (homogeneous), sites of pre-mRNA processing (speckled), and sites of pre-rRNA processing (nucleolus). They provided documented the structural and functional contexts for these three nuclear regions and discussed autoantigens and alarmins in each of them, hypothesizing that each region is potentially sufficient to induce self-reactive autoantibodies ( 12 – 14 ) and C1q/C1r/C1s dampen their immunogenicity ( 12 , 15 ).…”