Glucose and SIRT2 reciprocally mediate the regulation of keratin 8 by lysine acetylation.
Lysine acetylation is an important posttranslational modification that regulates microtubules and microfilaments, but its effects on intermediate filament proteins (IFs) are unknown. We investigated the regulation of keratin 8 (K8), a type II simple epithelial IF, by lysine acetylation. K8 was basally acetylated and the highly conserved Lys-207 was a major acetylation site. K8 acetylation regulated filament organization and decreased keratin solubility. Acetylation of K8 was rapidly responsive to changes in glucose levels and was up-regulated in response to nicotinamide adenine dinucleotide (NAD) depletion and in diabetic mouse and human livers. The NAD-dependent deacetylase sirtuin 2 (SIRT2) associated with and deacetylated K8. Pharmacologic or genetic inhibition of SIRT2 decreased K8 solubility and affected filament organization. Inhibition of K8 Lys-207 acetylation resulted in site-specific phosphorylation changes of K8. Therefore, K8 acetylation at Lys-207, a highly conserved residue among type II keratins and other IFs, is up-regulated upon hyperglycemia and down-regulated by SIRT2. Keratin acetylation provides a new mechanism to regulate keratin filaments, possibly via modulating keratin phosphorylation.
Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. nsnider@umich.edu
Natasha T
NT
Snider
Jessica M
JM
Leonard
Raymond
R
Kwan
Nicholas W
NW
Griggs
Liangyou
L
Rui
M Bishr
MB
Omary
D000107:Acetylation / Q000187:drug effects; D000818:Animals; D002460:Cell Line; D017124:Conserved Sequence; D005260:Female; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D007382:Intermediate Filaments / Q000378:metabolism; D053533:Keratin-8 / Q000235:genetics / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D056565:Sirtuin 2 / Q000378:metabolism*; D012995:Solubility / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
D053533:Keratin-8; D056565:Sirtuin 2; D005947:Glucose; D008239:Lysine