Background
Deconjugating enzymes (DCEs) are proteases that process ubiquitin or ubiquitin-like gene products, reverse the modification of proteins by a single ubiquitin or ubiquitin-like protein (UBL) and remodel polyubiquitin (or poly-UBL) chains on target proteins (Reyes-Turcu et al., 2009). The deubiquitylating - or deubiquitinating - enzymes (DUBs) represent the largest family of DCEs and regulate ubiquitin dependent signalling pathways. The activities of the DUBs include the generation of free ubiquitin from precursor molecules, the recycling of ubiquitin following substrate degradation to maintain cellular ubiquitin homeostasis and the removal of ubiquitin or ubiquitin-like proteins (UBL) modifications through chain editing to rescue proteins from proteasomal degradation or to influence cell signalling events (Komander et al., 2009). There are two main classes of DUB; cysteine proteases and metalloproteases. AMSH-Like Protein (AMSH-LP) is a member of the JAB1/MPN/Mov34 metalloenzyme (JAMM) family and cloning of the human gene was first described by Nagase et al. (2000). AMSH and AMSH-LP share 54% identity and 75% sequence similarity in their JAMM domain. It is known that both proteins act as regulators of free ubiquitin in the cell, bind clathrin, contain a putative nuclear localization signal and an MIT domain. However, AMSH-LP lacks some of the key features when compared to AMSH. AMSH contains an SH3-binding motif, which facilitates its interaction with STAM of ESCRT (endosomal sorting complexes required for transport), while a functional SH3-binding motif is lost in AMSH-LP (Davies et al., 2011). AMSH-LP is known to specifically cleave Lys 63-linked polyubiquitin chains and does not cleave Lys 48-linked polyubiquitin chains (Sato et al., 2008). After removal of these K63-linked polyubiquitin chains, AMSH-LP can coordinate the recycling of receptors to the cell surface (McCullough et al., 2004). AMSH-LP has been found to be a positive regulator of Tax activation of NF-κB. AMSH-LP indirectly stabilized Tax by promoting its shuttling from the nucleus to the cytoplasm, thereby protecting Tax from K48-induced ubiquitylation and proteasomal degradation in the nucleus. Thus, AMSH-LP is a DUB that controls Tax trafficking in the cell and is essential for exporting Tax from the nucleus to the cytoplasm, where it triggers IKK and NF-κB activation (Lavorgna and Harhaj, 2012).
References
Davies CW, Paul LN, Kim MI, Das C (2011) Structural and thermodynamic comparison of the catalytic domain of AMSH and AMSH-LP: nearly identical fold but different stability. J Mol Biol 413, 416-429.
Komander D, Clague MJ, Urbe S (2009) Breaking the chains: structure and function of the deubiquitinases. Nat Rev Mol Cell Biol 10, 550-563.
Lavorgna A, Harhaj EW (2012) An RNA Interference Screen Identifies the Deubiquitinase STAMBPL1 as a Critical Regulator of Human T-Cell Leukemia Virus Type 1 Tax Nuclear Export and NF-kappaB Activation. J Virol 86, 3357-3369.
McCullough J, Clague MJ, Urbe S (2004) AMSH is an endosome-associated ubiquitin isopeptidase. J Cell Biol 166, 487-492.
Nagase T, Kikuno R, Ishikawa KI, Hirosawa M, Ohara O (2000) Prediction of the coding sequences of unidentified human genes. XVI. The complete sequences of 150 new cDNA clones from brain which code for large proteins in vitro. DNA Res 7, 65-73.
Reyes-Turcu FE, Ventii KH, Wilkinson KD (2009) Regulation and cellular roles of ubiquitin-specific deubiquitinating enzymes. Ann Rev Biochem 78, 363-397.
Sato Y, Yoshikawa A, Yamagata A, Mimura H, Yamashita M, Ookata K, Nureki O, Iwai K, Komada M and Fukai S (2008) Structural basis for specific cleavage of Lys 63-linked polyubiquitin chains. Nature 455, 358-362.