Lamins and Lamin-Associated Proteins in Gastrointestinal Health and Disease

Brady, Graham F.; Kwan, Raymond; Cunha, Juliana Bragazzi; Elenbaas, Jared S.; Omary, M. Bishr

doi:10.1053/j.gastro.2018.03.026

Cited by 31 publications

(41 citation statements)

References 180 publications

(205 reference statements)

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“…A truncated lamin A causes a premature aging syndrome of Hutchinson-Gilford progeria. Consistent with our findings, expression of mutant lamin activated IFN-I response 49 . Additionally, recent reports suggest that lamins play important roles in both the outside-in and inside-out signaling processes.…”

Section: Discussionsupporting

confidence: 92%

Cellular Stress Signaling Activates Type-I IFN Response Through FOXO3-regulated Lamin Posttranslational Modification

Hwang

Dai

et al. 2020

Preprint

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Neural stem/progenitor cells (NSPCs) persist over the lifespan while encountering constant challenges from age or injury related brain environmental changes, including elevated oxidative stress. A time-dependent stress response that regulates the dynamic balance between quiescence and differentiation is thus essential to preserve NSPC long-term regenerative potential. Here we report that acutely elevated cellular oxidative stress in NSPCs suppresses neurogenic differentiation through induction of FOXO3mediated cGAS/STING and type I interferon (IFN-I) responses. We show that oxidative stress activates FOXO3 promoting upregulation of its transcriptional target glycine-Nmethyltransferase (GNMT) and thus depletion of s-adenosylmethionine (SAM), a key co-substrate involved in methyl group transfer reactions. Mechanistically, we demonstrate that reduced intracellular SAM availability disrupts carboxymethylation and maturation of nuclear lamin, which trigger cytosolic release of chromatin fragments and subsequent activation of the cGAS/STING/IFN-I cascade. Together, our findings suggest the FOXO3-GNMT/SAM-lamin-cGAS/STING-IFN-I signaling cascade as a critical stress response program that preserves its long-term regenerative potential.

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Section: Discussionsupporting

confidence: 92%

Cellular Stress Signaling Activates Type-I IFN Response Through FOXO3-regulated Lamin Posttranslational Modification

Hwang

Dai

et al. 2020

Preprint

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“…Interestingly, some literatures regarding the influence of lamins on premature senescence and liver diseases are controversial. For instance, the disruption or mutantion of lamins led to hepatocytes abnormal differentiation and premature aging to induce steatohepatitis [7]. Progerin, a mutant of Lamin A, is deemed to a moderator for premature aging and dysfunction in endothelial cells [19].…”

Section: Discussionmentioning

confidence: 99%

“…Novel findings show that lamins and their associated proteins, which regulate nucleoskeleton and cytoskeleton, affect cellular differentiation and senescence [7,8]. Especially, progerin is a mutant Lamin A protein, and its accumulation brings about abnormal nucleoskeleton and cell premature senescence to promote the occurrence and development of chronic liver diseases [7][8][9]. Thus, we speculate that progerin may contribute to premature senescence-associated defenestration in HSECs, via abnormal cytoskeleton remodeling.…”

Section: Introductionmentioning

confidence: 86%

“…Our previous studies reveal that oxidative stress facilitates defenestration in HSECs via F-actin remodeling in liver fibrogenesis [5,6]. Novel findings show that lamins and their associated proteins, which regulate nucleoskeleton and cytoskeleton, affect cellular differentiation and senescence [7,8]. Especially, progerin is a mutant Lamin A protein, and its accumulation brings about abnormal nucleoskeleton and cell premature senescence to promote the occurrence and development of chronic liver diseases [7][8][9].…”

Section: Introductionmentioning

confidence: 95%

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SIRT1 ameliorates premature senescence-induced defenestration in hepatic sinusoidal endothelial cell

Bai

et al. 2020

Preprint

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Premature senescence, linked to progerin, involves in endothelial dysfunction and liver diseases. Activating sirtuin 1 (SIRT1) ameliorates liver fibrosis. However, the potential mechanisms of premature senescence in defenestration in hepatic sinusoidal endothelial cells (HSECs) and how SIRT1 affects fenestrae remains elusive. Our study showed that in vivo, premature senescence occurred, with decrease of SIRT1, during CCl 4 -induced defenestration in HSECs and liver fibrogenesis; whereas overexpressing SIRT1 with adenovirus vector lessened progerin-associated premature senescence to relieve CCl 4 -induced defenestration and liver fibrosis. In vitro, fenestrae in HSECs disappeared, with progerin-associated premature senescence; these effects aggravated by H 2 O 2 -induced oxidative damage. Nevertheless, knockdown of NOX2 or overexpression of SIRT1 with adenovirus vector reduced progerin-associated premature senescence to maintain fenestrae through deacetylating p53. Furthermore, more Ac p53 K381 and progerin co-localized with accumulation of actin filament (F-actin) in the nuclear envelope of H 2 O 2 -treated HSECs; in contrast, these effects were rescued by overexpressing SIRT1. In conclusion, NOX2-dependent oxidative damage aggravates defenestration in HSECs via progerin-associated premature senescence; SIRT1-mediated deacetylation of p53 maintains fenestrae and attenuates liver fibrogenesis through inhibiting premature senescence.

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“…More than 400 rare LMNA variants, predominantly missense, but also small indels, splicing and nonsense variants, have been associated with numerous, distinct multisystem disorders. 28 There are few if any examples of rare variants in a single gene underlying such a qualitatively wide range of disparate clinical phenotypes, affecting in specific manner combinations of a wide range of tissues and organ systems. 29 A-type laminopathies include MD, neuropathies, cardiomyopathies, aging and metabolic disorders and various combinations of elements of these syndromes and conditions ( LMNA gene ( Figure 1).…”

Section: A-type Laminopathiesmentioning

confidence: 99%

Complex effects of laminopathy mutations on nuclear structure and function

Hegele

2018

Clinical Genetics

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The nuclear lamins are important members of the intermediate filament (IF) family of proteins, involved in structural support and regulation of the nuclear lamina. Different mutations in various members of these type V IF proteins produce a staggering range of human disease phenotypes, which collectively have been termed “laminopathies.” Compelling examples are the wide range of inherited disorders that result from rare variants in LMNA encoding lamin A/C. These laminopathies include skeletal and cardiac muscle disorders, neuropathies, multisystem progeroid disorders, and lipodystrophies, of which the latter are associated with several metabolic complications. Functions of lamin A/C that have been shown to be compromised by distinct mutations in LMNA include loss of nuclear structural integrity, altered interaction with transcription factors, and changes to post‐translational processing of pre‐lamins. Recently, evidence has emerged that certain LMNA mutations, such as those causing partial lipodystrophy, alter the interaction between chromatin and lamin A, in turn affecting the spatial orientation and distribution of chromatin within the nucleus. Because chromatin organization is exquisitely tied to global patterns of gene expression, the findings suggest a novel mechanism to explain the tissue‐specific impact of a subset of laminopathy‐associated LMNA mutations.

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Lamins and Lamin-Associated Proteins in Gastrointestinal Health and Disease

Cited by 31 publications

References 180 publications

Cellular Stress Signaling Activates Type-I IFN Response Through FOXO3-regulated Lamin Posttranslational Modification

Cellular Stress Signaling Activates Type-I IFN Response Through FOXO3-regulated Lamin Posttranslational Modification

SIRT1 ameliorates premature senescence-induced defenestration in hepatic sinusoidal endothelial cell

Complex effects of laminopathy mutations on nuclear structure and function

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