Ubiquitination of lysine-331 by Kaposi's sarcoma-associated herpesvirus protein K5 targets HFE for lysosomal degradation.
The nonclassical MHC class I-related (MHC-I) molecule HFE controls cellular iron homeostasis by a mechanism that has not been fully elucidated. We examined the regulation of HFE by K5, the E3 ubiquitin ligase encoded by Kaposi's sarcoma-associated herpesvirus (KSHV/HHV8), that is known to down-regulate classical MHC-I. K5 down-regulated HFE efficiently, using polyubiquitination of the membrane proximal lysine in the HFE cytoplasmic tail (K331), to target the molecule for degradation via ESCRT1/TSG101-dependent sorting from endosomes to multivesicular bodies (MVBs)/lysosomes. In the primary effusion lymphoma cell line BC-3, which carries latent KSHV, HFE was degraded rapidly upon virus reactivation. HFE was ubiquitinated on lysine-331 in unactivated BC-3 cells, conditions where K5 was not detectable, consistent with an endogenous E3 ubiquitin ligase controlling HFE expression. The results show regulated expression of HFE by ubiquitination, consistent with a role in cellular iron homeostasis, a molecular mechanism targeted by KSHV to achieve a positive iron balance.
Rhodes
David A
DA
Department of Pathology, Immunology Division, University of Cambridge, Cambridge Institute for Medical Research, Cambridge CB2 0XY, United Kingdom.
Boyle
Louise H
LH
Boname
Jessica M
JM
Lehner
Paul J
PJ
Trowsdale
John
J
D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000378:metabolism; D002460:Cell Line; D017124:Conserved Sequence; D000071020:Hemochromatosis Protein; D019288:Herpesvirus 8, Human / Q000378:metabolism*; D015395:Histocompatibility Antigens Class I / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism*; D008239:Lysine / Q000235:genetics / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism*; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D011990:Receptors, Transferrin / Q000378:metabolism; D014168:Transferrin / Q000378:metabolism; D025801:Ubiquitin; D054875:Ubiquitination
D015703:Antigens, CD; C068126:CD71 antigen; C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D017874:Immediate-Early Proteins; C405867:K5 protein, Human herpesvirus 8; D008565:Membrane Proteins; D011990:Receptors, Transferrin; D014168:Transferrin; D025801:Ubiquitin; D008239:Lysine
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