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

Buerger, Stefanie; Herrmann, Valerie L.; Mundt, Sarah; Trautwein, Nico; Groettrup, Marcus; Basler, Michael

doi:10.4049/jimmunol.1500592

Cited by 24 publications

(26 citation statements)

References 40 publications

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“…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.…”

Section: Discussionmentioning

confidence: 99%

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

Nguyen

Now

Kim

et al. 2016

Sci Rep

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RIG-I is a key cytosolic RNA sensor that mediates innate immune defense against RNA virus. Aberrant RIG-I activity leads to severe pathological states such as autosomal dominant multi-system disorder, inflammatory myophathies and dermatomyositis. Therefore, identification of regulators that ensure efficient defense without harmful immune-pathology is particularly critical to deal with RIG-I-associated diseases. Here, we presented the inflammatory inducible FAT10 as a novel negative regulator of RIG-I-mediated inflammatory response. In various cell lines, FAT10 protein is undetectable unless it is induced by pro-inflammatory cytokines. FAT10 non-covalently associated with the 2CARD domain of RIG-I, and inhibited viral RNA-induced IRF3 and NF-kB activation through modulating the RIG-I protein solubility. We further demonstrated that FAT10 was recruited to RIG-I-TRIM25 to form an inhibitory complex where FAT10 was stabilized by E3 ligase TRIM25. As the result, FAT10 inhibited the antiviral stress granules formation contains RIG-I and sequestered the active RIG-I away from the mitochondria. Our study presented a novel mechanism to dampen RIG-I activity. Highly accumulated FAT10 is observed in various cancers with pro-inflammatory environment, therefore, our finding which uncovered the suppressive effect of the accumulated FAT10 during virus-mediated inflammatory response may also provide molecular clue to understand the carcinogenesis related with infection and inflammation.

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Section: Discussionmentioning

confidence: 99%

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

Nguyen

Now

Kim

et al. 2016

Sci Rep

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“…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.…”

Section: Fat10 In Adaptive and Innate Immunitymentioning

confidence: 97%

“…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.…”

Section: Introductionmentioning

confidence: 99%

The ubiquitin-like modifier FAT10 in cancer development

Aichem

Groettrup

2016

The International Journal of Biochemistry & Cell Biology

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a b s t r a c tDuring the last years it has emerged that the ubiquitin-like modifier FAT10 is directly involved in cancer development. FAT10 expression is highly up-regulated by pro-inflammatory cytokines IFN-␥ and TNF-␣ in all cell types and tissues and it was also found to be up-regulated in many cancer types such as glioma, colorectal, liver or gastric cancer. While pro-inflammatory cytokines within the tumor microenvironment probably contribute to FAT10 overexpression, an increasing body of evidence argues that pro-malignant capacities of FAT10 itself largely underlie its broad and intense overexpression in tumor tissues. FAT10 thereby regulates pathways involved in cancer development such as the NF-B-or Wnt-signaling. Moreover, FAT10 directly interacts with and influences downstream targets such as MAD2, p53 or ␤-catenin, leading to enhanced survival, proliferation, invasion and metastasis formation of cancer cells but also of non-malignant cells. In this review we will provide an overview of the regulation of FAT10 expression as well as its function in carcinogenesis.

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“…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).…”

Section: Introductionmentioning

confidence: 99%

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

Boehm

Bialas

Catone

et al. 2020

Journal of Biological Chemistry

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The retina-specific chaperone AIPL1 is essential for the correct assembly of phosphodiesterase 6 (PDE6), which is a pivotal effector enzyme for phototransduction and vision because it hydrolyzes cGMP. AIPL1 interacts with the cytokine-inducible ubiquitin-like modifier FAT10 that gets covalently conjugated to hundreds of proteins and targets its conjugation substrates for proteasomal degradation, but whether FAT10 affects PDE6 function or turnover is unknown. Here, we show that FAT10 mRNA is expressed in human retina and identify rod PDE6 as a retina-specific substrate of FAT10 conjugation. We found that AIPL1 stabilizes the FAT10 monomer as well as the PDE6-FAT10 conjugate. Additionally, we elucidated the functional consequences of PDE6 FAT10ylation. On the one hand, we demonstrate that FAT10 targets PDE6 for proteasomal degradation by formation of a covalent isopeptide linkage. On the other hand, FAT10 inhibits PDE6 cGMP hydrolyzing activity by non-covalently interacting with the PDE6 GAFa and catalytic domains. Therefore, FAT10 may contribute to loss of PDE6 and, as a consequence, degeneration of retinal cells in eye diseases linked to inflammation and inherited blindness causing mutations in AIPL1.

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

Cited by 24 publications

References 40 publications

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

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

The ubiquitin-like modifier FAT10 in cancer development

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

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