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Role of the ubiquitin-like modifier FAT10 in protein degradation and ...

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Introduction<br />

diglyc<strong>in</strong>e-deficient mutant <strong>of</strong> <strong>FAT10</strong> revealed that conjugation to a substrate was<br />

not required for its <strong>degradation</strong> (Hipp, 2004). In addition, <strong>the</strong> <strong>degradation</strong> <strong>of</strong><br />

<strong>FAT10</strong> could be fur<strong>the</strong>r accelerated through coexpression <strong>of</strong> a non-covalent <strong>in</strong>ter-<br />

action partner, <strong>the</strong> UBL-UBA doma<strong>in</strong> prote<strong>in</strong> NUB1L (Hipp et al., 2004). Despite<br />

<strong>the</strong> strik<strong>in</strong>g similarities between <strong>ubiquit<strong>in</strong></strong>- <strong>and</strong> <strong>FAT10</strong>-mediated <strong>degradation</strong>,<br />

FATylation <strong>of</strong> a prote<strong>in</strong> appears to be sufficient to promote its <strong>degradation</strong>, as<br />

two experimental approaches demonstrated no fur<strong>the</strong>r requirement for ubiquity-<br />

lation. A mutant version <strong>of</strong> <strong>FAT10</strong>, which due to a lack <strong>of</strong> lys<strong>in</strong>es is unable to<br />

serve as a substrate <strong>of</strong> <strong>ubiquit<strong>in</strong></strong> conjugation, was still able to promote <strong>the</strong> degra-<br />

dation <strong>of</strong> a model substrate. Likewise, a cell l<strong>in</strong>e carry<strong>in</strong>g a <strong>the</strong>rmolabile mutant<br />

<strong>of</strong> <strong>the</strong> major <strong>ubiquit<strong>in</strong></strong>-activat<strong>in</strong>g enzyme showed no accumulation <strong>of</strong> an artificial<br />

<strong>FAT10</strong>-conjugate (Hipp et al., 2005).<br />

Evidence for a role <strong>of</strong> <strong>FAT10</strong> <strong>in</strong> immunity has rema<strong>in</strong>ed sparse. In fact, <strong>the</strong> only<br />

two connections to <strong>the</strong> immune response derive from <strong>the</strong> study <strong>of</strong> <strong>FAT10</strong> gene-<br />

targeted mice, which display a hypersensitivity to LPS as <strong>the</strong>ir major phenotype<br />

to date (Canaan et al., 2006), <strong>and</strong> <strong>the</strong> f<strong>in</strong>d<strong>in</strong>g that <strong>FAT10</strong> might be able to <strong>in</strong>hibit<br />

hepatitis B virus expression <strong>in</strong> a hepatoblastoma cell l<strong>in</strong>e (Xiong et al., 2003).<br />

A recent number <strong>of</strong> publications have, however, implicated <strong>FAT10</strong> <strong>in</strong> cancer, al-<br />

though it is still a matter <strong>of</strong> debate whe<strong>the</strong>r it functions as a tumor suppressor or<br />

ra<strong>the</strong>r an oncogene.<br />

One study found <strong>FAT10</strong> to be highly upregulated <strong>in</strong> hepatocellular carc<strong>in</strong>oma as<br />

well as o<strong>the</strong>r cancers <strong>of</strong> <strong>the</strong> gastro<strong>in</strong>test<strong>in</strong>al tract <strong>and</strong> female reproductive sys-<br />

tem (Lee et al., 2003). Ano<strong>the</strong>r identified <strong>FAT10</strong> as a potential marker for liver<br />

preneoplasia, as it was highly overexpressed <strong>in</strong> a model <strong>of</strong> Mallory-Denk body<br />

conta<strong>in</strong><strong>in</strong>g chronic liver diseases, which are thought to progress to hepatocellular<br />

carc<strong>in</strong>oma (Oliva et al., 2008). Both suggested an active role <strong>of</strong> <strong>FAT10</strong> <strong>in</strong> tumori-<br />

genesis based on its <strong>in</strong>teraction with <strong>the</strong> sp<strong>in</strong>dle assembly checkpo<strong>in</strong>t prote<strong>in</strong><br />

MAD2 (Liu et al., 1999). Through non-covalent <strong>in</strong>teraction, <strong>FAT10</strong> is thought to<br />

displace MAD2 from <strong>the</strong> k<strong>in</strong>etochore dur<strong>in</strong>g prometaphase, which leads to faulty<br />

chromosomal segregation <strong>and</strong> ultimately results <strong>in</strong> <strong>the</strong> formation <strong>of</strong> cells conta<strong>in</strong>-<br />

<strong>in</strong>g abnormal chromosome numbers (Ren et al., 2006). This hypo<strong>the</strong>sis is fur<strong>the</strong>r<br />

corroborated by <strong>the</strong> f<strong>in</strong>d<strong>in</strong>g that <strong>the</strong> expression <strong>of</strong> <strong>FAT10</strong> is cell-cyle regulated<br />

at transcript level <strong>and</strong> is kept low <strong>in</strong> G2/M phase, presumably to prevent <strong>FAT10</strong><br />

from <strong>in</strong>terfer<strong>in</strong>g with chromosomal segregation (Lim et al., 2006).<br />

Strong evidence for <strong>the</strong> function <strong>of</strong> <strong>FAT10</strong> as a tumor suppressor, on <strong>the</strong> o<strong>the</strong>r<br />

h<strong>and</strong>, comes from <strong>the</strong> f<strong>in</strong>d<strong>in</strong>g that expression <strong>of</strong> <strong>FAT10</strong> is able to <strong>in</strong>duce caspase-<br />

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