The Ubiquitin-like Modifier FAT10 Is Selectively Expressed in Medullary Thymic Epithelial Cells and Modifies T Cell Selection

Abstract

HLA-F adjacent transcript 10 (FAT10) is a cytokine-inducible ubiquitin-like modifier that is highly expressed in the thymus and directly targets FAT10-conjugated proteins for degradation by the proteasome. High expression of FAT10 in the mouse thymus could be assigned to strongly autoimmune regulator–expressing, mature medullary thymic epithelial cells, which play a pivotal role in negative selection of T cells. Also in the human thymus, FAT10 is localized in the medulla but not the cortex. TCR Vβ-segment screening revealed a changed T cell repertoire in FAT10-deficient mice. Analysis of five MHC class I– and II–restricted TCR-transgenic mice demonstrated an altered thymic negative selection in FAT10-deficient mice. Furthermore, the repertoire of peptides eluted from MHC class I molecules was influenced by FAT10 expression. Hence, we identified FAT10 as a novel modifier of thymic Ag presentation and epitope-dependent elimination of self-reactive T cells, which may explain why the fat10 gene could recently be linked to enhanced susceptibility to virus-triggered autoimmune diabetes.

Ubiquitin-like modifier FAT10 attenuates RIG-I mediated antiviral signaling by segregating activated RIG-I from its signaling platform

“…In addition, FAT10 functions in the intracellular defense against bacteria by decorating cytoplasmic Salmonella Typhimurium that has been targeted for xenophagy 37 . Furthermore, FAT10-deficient mice are more sensitive to endotoxin challenge 38 , and FAT10 deletion in rats negatively affects virus-triggered autoimmune diabetes 39 , suggesting potential regulatory role of FAT10 during infection. The present study is the first to demonstrate this previously unreported function of FAT10 in an antiviral response.…”

The ubiquitin-like modifier FAT10 in cancer development

“…The high expression of FAT10 in the thymus could be allocated to medullary thymic epithelial cells (mTECs) and it was shown that FAT10 modifies thymic T-cell selection, probably due to an altered peptide presentation on MHC class I molecules (Buerger et al, 2015). Additional data point to a role of FAT10 in MHC class I antigen presentation.…”

“…Of all these ULMs, FAT10 is the only modifier which acts as an autonomous transferable signal for degradation by the 26S proteasome and it was shown that this process can occur independently of ubiquitin (Hipp et al, 2005;Schmidtke et al, 2009). FAT10 is a protein of the immune system and it is strongly up-regulated by pro-inflammatory cytokines (Fan et al, 1996;Raasi et al, 1999) and during the maturation of antigen presenting cells (Buerger et al, 2015;Ebstein et al, 2009;Lukasiak et al, 2008). Moreover, numerous recent publications point to a direct involvement of FAT10 in cancer development.…”

The ubiquitin-like modifier FAT10 inhibits retinal PDE6 activity and mediates its proteasomal degradation

“…We have recently published another interaction partner of AIPL1, human leukocyte antigen (HLA)-F adjacent transcript 10 (FAT10) protein (21). FAT10 belongs to the family of ubiquitin-like modifiers and is, in contrast to the ubiquitously expressed ubiquitin, constitutively expressed only in organs and unique cell types of the immune system (22)(23)(24)(25). In other cell types, FAT10 is expressed upon synergistic induction by the pro-inflammatory cytokines tumor necrosis factor (TNF)-α and interferon (IFN)-γ (26,27).…”