USP7 attenuates hepatic gluconeogenesis through modulation of FoxO1 gene promoter occupancy.
Hepatic forkhead protein FoxO1 is a key component of systemic glucose homeostasis via its ability to regulate the transcription of rate-limiting enzymes in gluconeogenesis. Important in the regulation of FoxO1 transcriptional activity are the modifying/demodifying enzymes that lead to posttranslational modification. Here, we demonstrate the functional interaction and regulation of FoxO1 by herpesvirus-associated ubiquitin-specific protease 7 (USP7; also known as herpesvirus-associated ubiquitin-specific protease, HAUSP), a deubiquitinating enzyme. We show that USP7-mediated mono-deubiquitination of FoxO1 results in suppression of FoxO1 transcriptional activity through decreased FoxO1 occupancy on the promoters of gluconeogenic genes. Knockdown of USP7 in primary hepatocytes leads to increased expression of FoxO1-target gluconeogenic genes and elevated glucose production. Consistent with this, USP7 gain-of-function suppresses the fasting/cAMP-induced activation of gluconeogenic genes in hepatocyte cells and in mouse liver, resulting in decreased hepatic glucose production. Notably, we show that the effects of USP7 on hepatic glucose metabolism depend on FoxO1. Together, these results place FoxO1 under the intimate regulation of deubiquitination and glucose metabolic control with important implication in diseases such as diabetes.
Departments of Cancer Biology, Dana-Farber Cancer Institute and Cell Biology, Harvard Medical School, Boston, Massachusetts 02115.
Jessica A
JA
Hall
Mitsuhisa
M
Tabata
Joseph T
JT
Rodgers
Pere
P
Puigserver
D000818:Animals; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D005943:Gluconeogenesis; D005947:Glucose / Q000096:biosynthesis; D057809:HEK293 Cells; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D015398:Signal Transduction; D014158:Transcription, Genetic; D000076084:Ubiquitin-Specific Peptidase 7; D064570:Ubiquitin-Specific Proteases / Q000502:physiology*; D054875:Ubiquitination
D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D000076084:Ubiquitin-Specific Peptidase 7; D064570:Ubiquitin-Specific Proteases; C579190:Usp7 protein, mouse; D005947:Glucose