SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells.
Sir2 is an NAD-dependent deacetylase that connects metabolism with longevity in yeast, flies, and worms. Mammals have seven Sir2 homologs (SIRT1-7). We show that SIRT4 is a mitochondrial enzyme that uses NAD to ADP-ribosylate and downregulate glutamate dehydrogenase (GDH) activity. GDH is known to promote the metabolism of glutamate and glutamine, generating ATP, which promotes insulin secretion. Loss of SIRT4 in insulinoma cells activates GDH, thereby upregulating amino acid-stimulated insulin secretion. A similar effect is observed in pancreatic beta cells from mice deficient in SIRT4 or on the dietary regimen of calorie restriction (CR). Furthermore, GDH from SIRT4-deficient or CR mice is insensitive to phosphodiesterase, an enzyme that cleaves ADP-ribose, suggesting the absence of ADP-ribosylation. These results indicate that SIRT4 functions in beta cell mitochondria to repress the activity of GDH by ADP-ribosylation, thereby downregulating insulin secretion in response to amino acids, effects that are alleviated during CR.
Haigis
Marcia C
MC
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
Mostoslavsky
Raul
R
Haigis
Kevin M
KM
Fahie
Kamau
K
Christodoulou
Danos C
DC
Murphy
Andrew J
AJ
Valenzuela
David M
DM
Yancopoulos
George D
GD
Karow
Margaret
M
Blander
Gil
G
Wolberger
Cynthia
C
Prolla
Tomas A
TA
Weindruch
Richard
R
Alt
Frederick W
FW
Guarente
Leonard
L
D000246:Adenosine Diphosphate Ribose / Q000378:metabolism; D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D031204:Caloric Restriction; D045744:Cell Line, Tumor; D015536:Down-Regulation; D005947:Glucose / Q000494:pharmacology; D005969:Glutamate Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D005973:Glutamine / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000201:enzymology*; D007515:Islets of Langerhans / Q000187:drug effects / Q000201:enzymology*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000201:enzymology; D009243:NAD / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D056564:Sirtuin 1; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D000596:Amino Acids; D007328:Insulin; D034741:RNA, Small Interfering; D005973:Glutamine; D009243:NAD; D000246:Adenosine Diphosphate Ribose; D005969:Glutamate Dehydrogenase; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D037761:Sirtuins; D005947:Glucose