Targeting RAS‐converting enzyme 1 overcomes senescence and improves progeria‐like phenotypes of ZMPSTE24 deficiency

Yao, Haidong; Chen, Xue; Kashif, Muhammad; Wang, Ting; Ibrahim, Mohamed X.; Tüksammel, Elin; Revêchon, Gwladys; Eriksson, Maria; Wiel, Clotilde; Bergö, Martin O.

doi:10.1111/acel.13200

Cited by 6 publications

(9 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous studies have reported that CAAX PTMs influence the protein levels of certain CAAX proteins, potentially by affecting protein turnover ( 28 , 30 , 31 ). Based on these reports, we evaluated the turnover rate of Ras2-CAAX variants using cycloheximide chase analysis ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Specific Disruption of Ras2 CAAX Proteolysis Alters Its Localization and Function

et al. 2023

View full text Add to dashboard Cite

show abstract

Section: Resultsmentioning

confidence: 99%

Specific Disruption of Ras2 CAAX Proteolysis Alters Its Localization and Function

et al. 2023

View full text Add to dashboard Cite

show abstract

“…However, Lmna L648R/L648R mice like Zmpste24 −/− mice with two wild-type Lmna alleles express roughly equal amounts of prelamin A relative to lamin C, so this explanation seems unlikely ( 12 , 13 ). Another possibility is that the single amino acid substitution renders the L648R variant less “toxic” than native prelamin A, and determining whether binding of this variant to the known prelamin A interactors, such as AKT and SUN1 ( 44 – 46 ), is diminished would be of interest to test in the future. However, this explanation is difficult to reconcile with the wealth of data suggesting that it is the farnesyl and carboxylmethyl moieties of prelamin A that are primarily responsible for its adverse effects in cultured cells and mice ( 45 – 47 ).…”

Section: Discussionmentioning

confidence: 99%

“…Another possibility is that the single amino acid substitution renders the L648R variant less “toxic” than native prelamin A, and determining whether binding of this variant to the known prelamin A interactors, such as AKT and SUN1 ( 44 – 46 ), is diminished would be of interest to test in the future. However, this explanation is difficult to reconcile with the wealth of data suggesting that it is the farnesyl and carboxylmethyl moieties of prelamin A that are primarily responsible for its adverse effects in cultured cells and mice ( 45 – 47 ). Furthermore, mice engineered to express only a nonfarnesylated prelamin A, without any lamin C, develop cardiomyopathy but do not have progeroid phenotypes and live much longer and have less severe growth retardation than Zmpste24 −/− mice ( 38 ).…”

Section: Discussionmentioning

confidence: 99%

Abolishing the prelamin A ZMPSTE24 cleavage site leads to progeroid phenotypes with near-normal longevity in mice

Wang

Shilagardi

Hsu

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Prelamin A is a farnesylated precursor of lamin A, a nuclear lamina protein. Accumulation of the farnesylated prelamin A variant progerin, with an internal deletion including its processing site, causes Hutchinson–Gilford progeria syndrome. Loss-of-function mutations in ZMPSTE24, which encodes the prelamin A processing enzyme, lead to accumulation of full-length farnesylated prelamin A and cause related progeroid disorders. Some data suggest that prelamin A also accumulates with physiological aging. Zmpste24−/− mice die young, at ∼20 wk. Because ZMPSTE24 has functions in addition to prelamin A processing, we generated a mouse model to examine effects solely due to the presence of permanently farnesylated prelamin A. These mice have an L648R amino acid substitution in prelamin A that blocks ZMPSTE24-catalyzed processing to lamin A. The LmnaL648R/L648R mice express only prelamin and no mature protein. Notably, nearly all survive to 65 to 70 wk, with ∼40% of male and 75% of female LmnaL648R/L648R mice having near-normal lifespans of 90 wk (almost 2 y). Starting at ∼10 wk of age, LmnaL648R/L648R mice of both sexes have lower body masses than controls. By ∼20 to 30 wk of age, they exhibit detectable cranial, mandibular, and dental defects similar to those observed in Zmpste24−/− mice and have decreased vertebral bone density compared to age- and sex-matched controls. Cultured embryonic fibroblasts from LmnaL648R/L648R mice have aberrant nuclear morphology that is reversible by treatment with a protein farnesyltransferase inhibitor. These novel mice provide a model to study the effects of farnesylated prelamin A during physiological aging.

show abstract

“…However, these defensive responses might eventually aggravate health span and accelerate the aging process, even leading to frequent embryonic lethality ( 29 , 36 , 38 ). Furthermore, we and others ( 33 ) have shown that activation of Akt/mTOR signaling is supposed to protect Zmpste24-deficient embryos from development failure possibly induced by genomic instability ( 6 ) or defective mitosis ( 16 , 17 ) or to largely rescue Zmpste24-deficient aging phenotypes by targeting the lipid modification of prelamin A ( 39 , 40 ).…”

Section: Discussionmentioning

confidence: 99%

Progerin modulates the IGF-1R/Akt signaling involved in aging

Jiang

Fang

et al. 2022

Sci. Adv.

View full text Add to dashboard Cite

Progerin, a product of LMNA mutation, leads to multiple nuclear abnormalities in patients with Hutchinson-Gilford progeria syndrome (HGPS), a devastating premature aging disorder. Progerin also accumulates during physiological aging. Here, we demonstrate that impaired insulin-like growth factor 1 receptor (IGF-1R)/Akt signaling pathway results in severe growth retardation and premature aging in Zmpste24 −/− mice, a mouse model of progeria. Mechanistically, progerin mislocalizes outside of the nucleus, interacts with the IGF-1R, and down-regulates its expression, leading to inhibited mitochondrial respiration, retarded cell growth, and accelerated cellular senescence. Pharmacological treatment with the PTEN (phosphatase and tensin homolog deleted on chromosome 10) inhibitor bpV (HOpic) increases Akt activity and improves multiple abnormalities in Zmpste24-deficient mice. These findings provide previously unidentified insights into the role of progerin in regulating the IGF-1R/Akt signaling in HGPS and might be useful for treating LMNA -associated progeroid disorders.

show abstract

Targeting RAS‐converting enzyme 1 overcomes senescence and improves progeria‐like phenotypes of ZMPSTE24 deficiency

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 6 publications

References 18 publications

Specific Disruption of Ras2 CAAX Proteolysis Alters Its Localization and Function

Specific Disruption of Ras2 CAAX Proteolysis Alters Its Localization and Function

Abolishing the prelamin A ZMPSTE24 cleavage site leads to progeroid phenotypes with near-normal longevity in mice

Progerin modulates the IGF-1R/Akt signaling involved in aging

Contact Info

Product

Resources

About