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NEDD8, ISG15 and FAT10


FAT10 is a small ubiquitin-like modifier that is encoded in the major histocompatibility complex and is synergistically inducible by tumor necrosis factor alpha and gamma-interferon. It is composed of two ubiquitin-like domains and possesses a free C-terminal diglycine motif that is required for the formation of FAT10 conjugates. FAT10 conjugates are rapidly degraded by the proteasome. Conjugation with FAT10 may thus provide an alternative ubiquitin-independent targeting mechanism for degradation by the proteasome, which is both cytokine inducible and irreversible. FAT10 has been shown to interact with the histone deacetylase HDAC6 which, in the absence of proteasomal degradation, may provide an alternative route to protein sequestration and removal by transporting conjugates to the aggresome. Again, as with ISG15 modification, a role in malignant transformation has been proposed.



NEDD8 is a small ubiquitin-like protein that can be conjugated to substrate-proteins in a process known as NEDDylation. Although NEDDylation plays a critical regulatory role in cell growth, viability, and development, the spectrum of NEDD8 substrates and its interaction network remains the subject of much investigation. Originally believed to modify only the cullin family members, it is now recognized that a large number of NEDD8 modified and associated proteins are involved in transcription, DNA repair and replication, cell cycle regulation and chromatin organization, and remodeling.


A lesser appreciated and understood member of the ubiquitin-like protein family is ISG15, a modifier encoded by an interferon stimulated gene. ISG15 has been ascribed important functions in various biological pathways from pregnancy to innate immune responses. Furthermore, ISG15 has been found to modify several important molecules and affect type I interferon signal transduction. Much further work is required in order to further elucidate the biological consequences of ISG15 and ISG15 modification, although its role in certain disease states such as malignant transformation has recently been proposed.


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