Deacetylation via SIRT2 prevents keratin-mutation-associated injury and keratin aggregation.

Sun J, Li P, Gui H, Rittié L, Lombard DB, Rietscher K, Magin TM, Xie Q, Liu L, Omary MB

JCI insight24 Jul 2023Cited by 3 (Europe PMC)

PMID37485877PMCIDPMC10443796DOI10.1172/jci.insight.166314PepBankPUB-37485877

Summary

Keratin (K) and other intermediate filament (IF) protein mutations at conserved arginines disrupt keratin filaments into aggregates and cause human epidermolysis bullosa simplex (EBS; K14-R125C) or predispose to mouse liver injury (K18-R90C). The challenge for more than 70 IF-associated diseases is the lack of clinically utilized IF-targeted therapies. We used high-throughput drug screening to identify compounds that normalized mutation-triggered keratin filament disruption. Parthenolide, a plant sesquiterpene lactone, dramatically reversed keratin filament disruption and protected cells and mice expressing K18-R90C from apoptosis. K18-R90C became hyperacetylated compared with K18-WT and treatment with parthenolide normalized K18 acetylation. Parthenolide upregulated the NAD-dependent SIRT2, and increased SIRT2-keratin association. SIRT2 knockdown or pharmacologic inhibition blocked the parthenolide effect, while site-specific Lys-to-Arg mutation of keratin acetylation sites normalized K18-R90C filaments. Treatment of K18-R90C-expressing cells and mice with nicotinamide mononucleotide had a parthenolide-like protective effect. In 2 human K18 variants that associate with human fatal drug-induced liver injury, parthenolide protected K18-D89H- but not K8-K393R-induced filament disruption and cell death. Importantly, parthenolide normalized K14-R125C-mediated filament disruption in keratinocytes and inhibited dispase-triggered keratinocyte sheet fragmentation and Fas-mediated apoptosis. Therefore, keratin acetylation may provide a novel therapeutic target for some keratin-associated diseases.

CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study2

2 results from studies that gave the peptide. No result from this study comes from people.

01AnimalAnimal study (in vivo)Efficacy outcome
In K18-R90C-expressing mice, NMN had a parthenolide-like protective effect.
In plain wordsIn mice expressing K18-R90C, NMN had a protective effect similar to parthenolide.
Peptide
NMN (nicotinamide mononucleotide)
Outcome
Direction not reportedProtective effect in K18-R90C models
Study
mousen: not reported in source
K18-R90C-expressing mice
Outcome group
Cell viability and death · Whole body
Studied dose
Dose not stated
Source sentences
Summary
Treatment of K18-R90C-expressing cells and mice with nicotinamide mononucleotide had a parthenolide-like protective effect.
Show in the study text Report a problemFND-3748587702
02LabIn vitro (cells)Efficacy outcome
In K18-R90C-expressing cells, NMN had a parthenolide-like protective effect.
In plain wordsIn cells expressing K18-R90C, NMN had a protective effect similar to parthenolide.
Peptide
NMN (nicotinamide mononucleotide)
Outcome
Direction not reportedProtective effect in K18-R90C models
Study
n: not reported in source
K18-R90C-expressing cells
Outcome group
Cell viability and death · Whole body
Studied dose
Dose not stated
Source sentences
Summary
Treatment of K18-R90C-expressing cells and mice with nicotinamide mononucleotide had a parthenolide-like protective effect.
Show in the study text Report a problemFND-3748587701

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Version history

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Version 2Current
21 Oct 2026, 15:58 UTC
Study results updated
Version 1
21 Oct 2026, 12:50 UTC
First added · source update from Europe PMC

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