AUF1 is involved in splenic follicular B cell maintenance

Abstract

BackgroundThe adenosine/uridine-rich element (ARE)-binding protein AUF1 functions to regulate the inflammatory response through the targeted degradation of cytokine and other mRNAs that contain specific AREs in their 3' noncoding region (3' NCR). To investigate the role of AUF1 in the immune system, we characterized the lymphoid compartments of AUF1-deficient mice.ResultsMice lacking AUF1 exhibit an altered proportion and size of splenic B cell subsets. We show prominent apoptosis in splenic B cell follicles and reduced expression of Bcl-2, A1, and Bcl-XL correlate with increased turnover and significant reduction in the number and proportion of splenic FO B cells in AUF1-deficient mice. In addition, AUF1-deficient mice exhibit a sharp decrease in splenic size and lymphocyte cellularity. Bone marrow transfer studies demonstrate that AUF1 deficiency induces cell-autonomous defects in mature B cell subsets but not in the overall number of splenocytes. Reconstitution of irradiated adult AUF1-deficient mice with wild-type bone marrow restores the proportion of FO and marginal zone (MZ) B cells, but does not rescue the decrease in the number of splenocytes. Functionally, AUF1-deficient mice mount an attenuated response to T cell-independent (TI) antigen, which correlates with impaired MZ B cell function.ConclusionThese data indicate that AUF1 is important in the maintenance of splenic FO B cells and adequate humoral immune responses.

AU-rich RNA binding proteins in hematopoiesis and leukemogenesis

“…19 AUF1 function is essential for normal lymphopoiesis ( Figure 1). Knockout mice that are deficient in all 4 AUF1 isoforms display decreased numbers of splenic T and B cells (especially follicular B cells) together with a modest expansion of the splenic marginal zone B-cell compartment 20 (Figure 1). The reduced numbers of follicular B cells is attributable to increased turnover and apoptosis, most probably arising as a consequence of decreased levels of prosurvival proteins, Bcl2, BclXl, and Bfl1/A1.…”

“…20 AUF1-deficient mice also display reduced IgG serum levels in response to T-independent antigen despite no impairment in germinal center formation and class switch recombination. 20 AUF1 associates with the nucleophosmin-anaplastic lymphoma kinase (NMP-ALK) fusion protein that results from the most common translocation, t(2;5)(p23;q35), found in anaplastic large cell lymphoma (ALCL) and some other lymphomas. 21 It colocalizes with NMP-ALK-containing granules where it is targeted for phosphorylation.…”

Hsp27 and F-Box Protein β-TrCP Promote Degradation of mRNA Decay Factor AUF1

“…For example, auf1 Ϫ/Ϫ mice present severe endotoxemia due to failure to degrade TNF-␣ and IL-1␤ mRNAs (12). These animals also present pruritic inflammatory skin disease characterized by elevated production of interleukin 2 (IL-2), tumor necrosis factor alpha (TNF-␣), and IL-1␤ (13), and they have reduced numbers of splenic follicular B cells (14). In monocytes exposed to endotoxin, p40 AUF1 promotes translation of TAK1 mRNA (15).…”

RNA-Binding Protein AUF1 Promotes Myogenesis by Regulating MEF2C Expression Levels

“…Although it suppresses the expression of Bcl-2 and/or cyclin D1, the discovery that AUF1 levels increase in many malignancies has led to the proposal that AUF1 contributes to cancer pathogenesis (16). By helping to maintain appropriately low levels of TNF-␣ and IL-1␤, AUF1 also appears to facilitate the response to inflammatory and immune agents; in this regard, AUF1 knockout mice develop atopic dermatitis and experience severe endotoxic shock following exposure to lipopolysaccharide (17)(18)(19). In addition, AUF1 knockout mice display a striking phenotype of accelerated aging, characterized by enhanced telomere erosion, increased levels of inflammatory cytokines, and the accumulation of senescent cells, and numerous developmental defects, such as altered skeletal and muscular systems (20).…”