The ubiquitin-like modifier FAT10 interacts with HDAC6 and localizes to aggresomes under proteasome inhibition.
During misfolded-protein stress, the cytoplasmic protein histone deacetylase 6 (HDAC6) functions as a linker between the dynein motor and polyubiquitin to mediate the transport of polyubiquitylated cargo to the aggresome. Here, we identify a new binding partner of HDAC6, the ubiquitin-like modifier FAT10 (also known as UBD), which is cytokine-inducible and - similar to ubiquitin - serves as a signal for proteasomal degradation. In vivo, the two proteins only interacted under conditions of proteasome impairment. The binding of HDAC6 to FAT10 was mediated by two separate domains: the C-terminal ubiquitin-binding zinc-finger (BUZ domain) of HDAC6 and its first catalytic domain, even though catalytic activity of HDAC6 was not required for this interaction. Both endogenous and ectopically expressed FAT10 as well as the model conjugate FAT10-GFP localized to the aggresome in a microtubule-dependent manner. Furthermore, FAT10-containing as well as ubiquitin-containing aggresomes were reduced in both size and number in HDAC6-deficient fibroblasts. We conclude that, if FAT10 fails to subject its target proteins to proteasomal degradation, an alternative route is taken to ensure their sequestration and possibly also their subsequent removal by transporting them to the aggresome via the association with HDAC6.
Kalveram
Birte
B
Department of Biology, Division of Immunology, University of Constance, Universitätsstrasse 10, 78457 Konstanz, Germany.
Schmidtke
Gunter
G
Groettrup
Marcus
M
D000818:Animals; D002460:Cell Line; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000378:metabolism; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D051379:Mice; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors; D014162:Transfection; D014452:Ubiquitins / Q000235:genetics / Q000378:metabolism*
D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D061988:Proteasome Inhibitors; C109184:UBD protein, human; D014452:Ubiquitins; D049452:Green Fluorescent Proteins; D046988:Proteasome Endopeptidase Complex; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde