The role of lamin B receptor in the regulation of senescence-associated secretory phenotype (SASP)

En, Atsuki; Takauji, Yuki; Ayusawa, Dai; Fujii, Michihiko

doi:10.1016/j.yexcr.2020.111927

Cited by 22 publications

(19 citation statements)

References 42 publications

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“…Of interest, the opening of the senescence-protector gene LBR [ 27 ] was superior in acute- and post-COVID-19 monocytes. LBR reduction has been related to diminished cellular cholesterol synthesis, alterations in the chromatin structure which limit the cell cycle progression and promotion of a SASP with upregulation of IL-6, IL-8 and CCL3 [ 55 ]. We found an SASP including IL1RAP, OASL and MX1 genes [ 26 ] significantly upregulated in acute COVID-19.…”

Section: Discussionmentioning

confidence: 99%

Alterations in Circulating Monocytes Predict COVID-19 Severity and Include Chromatin Modifications Still Detectable Six Months after Recovery

et al. 2021

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An early analysis of circulating monocytes may be critical for predicting COVID-19 course and its sequelae. In 131 untreated, acute COVID-19 patients at emergency room arrival, monocytes showed decreased surface molecule expression, including low HLA-DR, in association with an inflammatory cytokine status and limited anti-SARS-CoV-2-specific T cell response. Most of these alterations had normalized in post-COVID-19 patients 6 months after discharge. Acute COVID-19 monocytes transcriptome showed upregulation of anti-inflammatory tissue repair genes such as BCL6, AREG and IL-10 and increased accessibility of chromatin. Some of these transcriptomic and epigenetic features still remained in post-COVID-19 monocytes. Importantly, a poorer expression of surface molecules and low IRF1 gene transcription in circulating monocytes at admission defined a COVID-19 patient group with impaired SARS-CoV-2-specific T cell response and increased risk of requiring intensive care or dying. An early analysis of monocytes may be useful for COVID-19 patient stratification and for designing innate immunity-focused therapies.

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Section: Discussionmentioning

confidence: 99%

Alterations in Circulating Monocytes Predict COVID-19 Severity and Include Chromatin Modifications Still Detectable Six Months after Recovery

et al. 2021

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“…SIRT7 downregulation promotes the transcription and accumulation of the LINE1 retrotransposon (LINE1), which triggers the innate immune response through the cGAS-STING signaling pathway (Bi et al, 2020). Besides the decrease in SIRT7, the decrease in the laminar protein lamin B receptor (LBR) also causes dysregulation of heterochromatin and generation of cytoplasmic chromatin fragments (CCFs) to activate the cGAS-STING pathway in senescent cells (En et al, 2020).…”

Section:  Of mentioning

confidence: 99%

Roles of extracellular vesicles in the aging microenvironment and age‐related diseases

Yin

Chen

Wang

et al. 2021

J of Extracellular Vesicle

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Cellular senescence is a persistently hypoproliferative state with diverse stressors in a specific aging microenvironment. Senescent cells have a double-edged sword effect: they can be physiologically beneficial for tissue repair, organ growth, and body homeostasis, and they can be pathologically harmful in age-related diseases. Among the hallmarks of senescence, the SASP, especially SASP-related extracellular vesicle (EV) signalling, plays the leading role in aging transmission via paracrine and endocrine mechanisms. EVs are successful in intercellular and interorgan communication in the aging microenvironment and age-related diseases. They have detrimental effects on downstream targets at the levels of immunity, inflammation, gene expression, and metabolism. Furthermore, EVs obtained from different donors are also promising materials and tools for antiaging treatments and are used for regeneration and rejuvenation in cell-free systems. Here, we describe the characteristics of cellular senescence and the aging microenvironment, concentrating on the production and function of EVs in age-related diseases, and provide new ideas for antiaging therapy with EVs.

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“…For example, lamin A/C stabilization leads to the degradation of polycomb repressive complex 1 (PCR1), which promotes the Cdkn2a expression [ 16 ], while loss of lamin B1 and its receptor LBR1 induces senescence [ 17 ]. LBR1 reduction causes changes in the chromatin structure that upregulate in turn the expression of SASP factors, such as IL-6, IL-8, and MMP1 [ 18 ]. Relevant to brain aging, treatments with rapamycin or trehalose that restore dysfunctional autophagy in long-term cultured neurons ameliorate senescent features, including SA- β -gal activity, nuclear envelope alterations, and p16 INK4A expression [ 13 , 19 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

Enhanced Activity of Exportin‐1/CRM1 in Neurons Contributes to Autophagy Dysfunction and Senescent Features in Old Mouse Brain

Gorostieta-Salas

Moreno-Blas

Gerónimo‐Olvera

et al. 2021

Oxidative Medicine and Cellular Longevity

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Brain aging is characterized by dysfunctional autophagy and cellular senescence, among other features. While autophagy can either promote or suppress cellular senescence in proliferating cells, in postmitotic cells, such as neurons, autophagy impairment promotes cellular senescence. CRM1 (exportin-1/XPO1) exports hundreds of nuclear proteins into the cytoplasm, including the transcription factors TFEB (the main inducer of autophagy and lysosomal biogenesis genes) and STAT3, another autophagy modulator. It appears that CRM1 is a modulator of aging-associated senescence and autophagy, because pharmacological inhibition of CRM1 improved autophagic degradation in flies, by increasing nuclear TFEB levels, and because enhanced CRM1 activity is mechanistically linked to senescence in fibroblasts from Hutchinson–Gilford progeria syndrome patients and old healthy individuals; furthermore, the exogenous overexpression of CRM1 induced senescence in normal fibroblasts. In this work, we tested the hypothesis that impaired autophagic flux during brain aging occurs due to CRM1 accumulation in the brain. We found that CRM1 levels and activity increased in the hippocampus and cortex during physiological aging, which resulted in a decrease of nuclear TFEB and STAT3. Consistent with an autophagic flux impairment, we observed accumulation of the autophagic receptor p62/SQSTM1 in neurons of old mice, which correlated with increased neuronal senescence. Using an in vitro model of neuronal senescence, we demonstrate that CRM1 inhibition improved autophagy flux and reduced SA-β-gal activity by restoring TFEB nuclear localization. Collectively, our data suggest that enhanced CRM1-mediated export of proteins during brain aging perturbs neuronal homeostasis, contributing to autophagy impairment, and neuronal senescence.

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The role of lamin B receptor in the regulation of senescence-associated secretory phenotype (SASP)

Cited by 22 publications

References 42 publications

Alterations in Circulating Monocytes Predict COVID-19 Severity and Include Chromatin Modifications Still Detectable Six Months after Recovery

Alterations in Circulating Monocytes Predict COVID-19 Severity and Include Chromatin Modifications Still Detectable Six Months after Recovery

Roles of extracellular vesicles in the aging microenvironment and age‐related diseases

Enhanced Activity of Exportin‐1/CRM1 in Neurons Contributes to Autophagy Dysfunction and Senescent Features in Old Mouse Brain

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