Trib1 Is Overexpressed in Systemic Lupus Erythematosus, While It Regulates Immunoglobulin Production in Murine B Cells

Abstract

Systemic lupus erythematosus (SLE) is a severe and heterogeneous autoimmune disease with a complex genetic etiology, characterized by the production of various pathogenic autoantibodies, which participate in end-organ damages. The majority of human SLE occurs in adults as a polygenic disease, and clinical flares interspersed with silent phases of various lengths characterize the usual evolution of the disease in time. Trying to understand the mechanism of the different phenotypic traits of the disease, and considering the central role of B cells in SLE, we previously performed a detailed wide analysis of gene expression variation in B cells from quiescent SLE patients. This analysis pointed out an overexpression of TRIB1. TRIB1 is a pseudokinase that has been implicated in the development of leukemia and also metabolic disorders. It is hypothesized that Trib1 plays an adapter or scaffold function in signaling pathways, notably in MAPK pathways. Therefore, we planned to understand the functional significance of TRIB1 overexpression in B cells in SLE. We produced a new knock-in model with B-cell-specific overexpression of Trib1. We showed that overexpression of Trib1 specifically in B cells does not impact B cell development nor induce any development of SLE symptoms in the mice. By contrast, Trib1 has a negative regulatory function on the production of immunoglobulins, notably IgG1, but also on the production of autoantibodies in an induced model. We observed a decrease of Erk activation in BCR-stimulated Trib1 overexpressing B cells. Finally, we searched for Trib1 partners in B cells by proteomic analysis in order to explore the regulatory function of Trib1 in B cells. Interestingly, we find an interaction between Trib1 and CD72, a negative regulator of B cells whose deficiency in mice leads to the development of autoimmunity. In conclusion, the overexpression of Trib1 could be one of the molecular pathways implicated in the negative regulation of B cells during SLE.

Comprehensive identification of pleiotropic loci for body fat distribution using the NHGRI‐EBI Catalog of published genome‐wide association studies

“…The MHC complex is associated with various infections, autoimmune conditions, cancers, and neuropathies . TRIB1 is a pseudokinase that has been implicated with various malignancies, immune function, lipoprotein metabolism, and cellular differentiation and proliferation . VEGFA is essential for physiological and pathological angiogenesis .…”

The Pseudokinase TRIB1 in Immune Cells and Associated Disorders

“…These expanded CD8 + KLRG1 + cells exhibited a distinct transcriptomic profile from both progenitor and terminal exhausted CD8 T cell subsets. Interestingly, they confirmed the interaction of TRIB1 with MALT1, also found in a murine B cell line (CH12), and demonstrated that TRIB1 interaction destabilized the CARMA1/Bcl10/MALT1 (CBM) complex which participated in TCR signaling [ 29 , 66 ].…”

“…In a different gene expression dataset, TRIB1 was identified as overexpressed in patients on dialysis and those with chronic rejection [ 28 ]. Additionally, TRIB1 expression was found to be increased in B cells from patients with SLE both during clinically inactive disease and in quiescent patients [ 29 ]. SLE is a severe and heterogeneous systemic autoimmunity disease that mostly affects women and causes immune-mediated inflammation leading to glomerulonephritis and vasculitis.…”

“…Single cell RNAseq experiments from PBMCs confirm these results and highlight the higher frequency of TRIB1-expressing monocytes compared to other immune cells ( Figure 2 B). Previous studies have highlighted the potential role of TRIB1 in B and T lymphocytes, although further elucidation is required [ 29 , 30 ]. Additionally, in CD4 + Tregs, progress was previously made by our team, which has incited interest in investigating the role of TRIB1 in Treg cells [ 58 ].…”

TRIB3 promotes MYC-associated lymphoma development through suppression of UBE3B-mediated MYC degradation

“…Interestingly, the expression of TRIB2, another member of the pseudokinase family, is elevated in T-cell acute lymphoblastic leukemia (T-ALL) 23 , and TRIB2 has emerged as a regulator of thymocyte cellular proliferation 24 . TRIB1, the third member of this family, has a negative regulatory effect on immunoglobulin production in murine B cells 25 . However, the role of TRIB3 in lymphomagenesis remains uncharacterized.…”