Identification of seven new human MHC class I region genes around the HLA-F locus

Abstract

Using cDNA hybridization selection techniques, we identified seven new genes in a 280 kilobase YAC covering the HLA-F locus. The new genes were mapped back to the YAC by a combination of optical restriction mapping and pulse field gel electrophoresis. Northern analysis of individual clones demonstrated the presence of either different mRNA sizes or different expression patterns. Two of the cDNA clones were expressed only in lymphoid cell lines: one in Jurkat cells (T cell) and another in JY cells (B cell). All the genes lacked sequence similarity to any known classical and non-classical major histocompatibility complex (MHC) class I genes, indicating that the MHC class I region has more functions than anticipated. Of the seven new genes, one is highly similar (97%) to mouse 60S ribosomal protein, and another is homologous to diubiquitin proteins. Of the two G-coupled receptor-like cDNAs, one was fully sequenced and found to be an olfactory receptor-like gene. The study strengthens evidence that the MHC complex not only plays a key role in the immune system, but also contributes to non-immunological functions.

USE1 is a bispecific conjugating enzyme for ubiquitin and FAT10, which FAT10ylates itself in cis

“…FAT10 is a very young member of the ubiquitin family, young in terms of evolution as it is found only in mammals, and young in terms of the history of investigation, beginning with its discovery in the histocompatibility complex class I locus in 1996 25 . In this study, we identify an E2 enzyme for FAT10, as well as the fi rst substrate of FAT10 conjugation, and show that it is the same protein, USE1.…”

The ubiquitin-like modifier FAT10 in cancer development

“…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 Fat10 gene (originally designated Ubiquitin D (Ubd)) was identified by genomic sequencing of the human major histocompatibility complex (MHC) by Sherman Weissman and colleagues in 1996 (Fan et al, 1996). The structural model of the 165 amino acid long, 18 kDa protein FAT10 as well as a previously published NMR structure of the N-terminal ubiquitin-like domain of FAT10 predicts two ubiquitin-like domains, both with a typical ␤-grasp fold.…”

“…The structural model of the 165 amino acid long, 18 kDa protein FAT10 as well as a previously published NMR structure of the N-terminal ubiquitin-like domain of FAT10 predicts two ubiquitin-like domains, both with a typical ␤-grasp fold. The Nand C-terminal ubiquitin-like domains are 29% and 36% identical to ubiquitin, respectively, arranged in a tandem array and separated by a short linker (Fan et al, 1996;Groettrup et al, 2008;Theng et al, 2014). In contrast to ubiquitin and other ubiquitin-like modifiers which are expressed as inactive precursors and which need to be activated by proteolytic processing at their C-terminus by specific proteases (Kerscher et al, 2006), FAT10 is already synthesized as a mature protein with a free diglycine motif at its C-terminus and can directly be activated and conjugated to substrate proteins (Raasi et al, 2001).…”

Mechanistic Studies on Activation of Ubiquitin and Di-ubiquitin-like Protein, FAT10, by Ubiquitin-like Modifier Activating Enzyme 6, Uba6

“…Interestingly, Uba6 was also found to be uniquely capable of activating a second UBL called FAT10 (13). FAT10, human leukocyte antigen F-associated transcript 10, is an 18-kDa protein that contains two ubiquitin-like domains that share 29 and 36% sequence identity with ubiquitin, respectively (16). The expression of FAT10 is induced by tumor necrosis factor-␣ (TNF-␣) and interferon-␥ (IFN␥) (17).…”