Cytoplasmic Chromatin Fragments and NF-κB Activation Depend on the Nuclear Pore Protein TPR during Oncogene-Induced Senescence

Core Concepts

TPR, a nuclear pore protein, is required for the formation of cytoplasmic chromatin fragments and early activation of NF-κB signaling during the stress response phase of oncogene-induced senescence, prior to the senescence-associated secretory phenotype.

Abstract

The study investigates the role of the nuclear pore protein TPR in the activation of NF-κB signaling and the formation of cytoplasmic chromatin fragments (CCFs) during the early stages of oncogene-induced senescence (OIS) in IMR90 fibroblasts.
Key findings:

TPR-dependent senescence-specific enhancers near SASP genes are enriched for binding sites of NF-κB and other inflammatory transcription factors.
Prolonged loss of TPR during senescence blocks NF-κB activation, which occurs prior to the senescence-associated secretory phenotype (SASP).
TPR knockdown reduces the formation of CCFs, which are thought to trigger innate immune signaling via the cGAS-STING pathway upstream of NF-κB.
TPR depletion decreases the expression of STING and reduces phosphorylation of the downstream kinase TBK1 during the early stages of OIS, before SASP activation.

These results suggest that TPR plays a key role in the loss of nuclear integrity and the generation of cytoplasmic chromatin during the initial stress response phase of senescence, which then triggers the inflammatory NF-κB-dependent SASP program. The study provides insights into the mechanisms linking nuclear organization, chromatin dynamics, and innate immune signaling in the senescence process.

Stats

"TPR is necessary for heterochromatin exclusion at nuclear pores."
"Knockdown of TPR in RAS cells blocks SAHF formation."
"Knockdown of TPR in RAS cells results in reduced nuclear localization of NF-κB."
"Knockdown of TPR in RAS cells decreases phosphorylation of NF-κB and IKK."
"Knockdown of TPR in RAS cells at day 3 and day 5 decreases nuclear intensity of NF-κB."
"Knockdown of TPR in RAS cells at day 3 and day 5 decreases phosphorylation of NF-κB and IKK."
"Knockdown of TPR in RAS cells decreases the frequency of detectable cytoplasmic chromatin fragments."

Quotes

"TPR is necessary for heterochromatin exclusion at nuclear pores and we have previously shown that TPR anchored at the nuclear pore is necessary for both the formation and maintenance of SAHF, as well as for activation of the SASP, during OIS without affecting cell cycle exit."
"Our data suggest that TPR at the nuclear pore is involved in the loss of structural integrity of the nuclear periphery during senescence. We propose that this acts as a trigger for activation of cytoplasmic nucleic acid sensing, NF-κB signalling, and activation of the SASP, during senescence."

Key Insights Distilled From

TPR is required for cytoplasmic chromatin fragment formation during senescence

by Bartlett,B. ... at www.biorxiv.org 04-18-2024

https://www.biorxiv.org/content/10.1101/2024.04.18.590085v1

Deeper Inquiries

How might the role of TPR in nuclear organization and chromatin dynamics be exploited for therapeutic interventions targeting senescence-associated pathologies?

TPR plays a crucial role in the regulation of nuclear organization and chromatin dynamics during senescence. Its involvement in the formation of cytoplasmic chromatin fragments (CCFs) and the activation of innate immune signaling pathways, such as the cGAS-STING pathway and NF-κB signaling, highlights its significance in the senescence process. Exploiting the role of TPR for therapeutic interventions targeting senescence-associated pathologies could involve several strategies:

Targeting TPR for modulation: Developing small molecules or peptides that can specifically target TPR and modulate its function could be a potential therapeutic approach. By regulating TPR activity, it may be possible to influence the formation of CCFs, the activation of innate immune responses, and the expression of SASP genes during senescence.

Drug development: Identifying compounds that can mimic or enhance the effects of TPR in regulating nuclear architecture and chromatin dynamics could lead to the development of novel drugs for senescence-related conditions. These compounds could target pathways downstream of TPR, such as the cGAS-STING pathway or NF-κB signaling, to modulate the senescence-associated phenotype.

Gene therapy: Utilizing gene editing technologies to manipulate TPR expression or function in senescent cells could offer a targeted approach to alter nuclear organization and chromatin structure. By restoring or enhancing TPR activity, it may be possible to mitigate the effects of senescence and associated pathologies.

Combination therapies: Combining TPR-targeted interventions with existing senolytic therapies or other approaches targeting senescence could lead to synergistic effects and improved outcomes. By addressing multiple aspects of senescence, including nuclear architecture and inflammatory signaling, a combination therapy approach may offer enhanced therapeutic benefits.

How might the role of TPR in nuclear organization and chromatin dynamics be exploited for therapeutic interventions targeting senescence-associated pathologies?

TPR plays a crucial role in the regulation of nuclear organization and chromatin dynamics during senescence. Its involvement in the formation of cytoplasmic chromatin fragments (CCFs) and the activation of innate immune signaling pathways, such as the cGAS-STING pathway and NF-κB signaling, highlights its significance in the senescence process. Exploiting the role of TPR for therapeutic interventions targeting senescence-associated pathologies could involve several strategies:

Targeting TPR for modulation: Developing small molecules or peptides that can specifically target TPR and modulate its function could be a potential therapeutic approach. By regulating TPR activity, it may be possible to influence the formation of CCFs, the activation of innate immune responses, and the expression of SASP genes during senescence.

Drug development: Identifying compounds that can mimic or enhance the effects of TPR in regulating nuclear architecture and chromatin dynamics could lead to the development of novel drugs for senescence-related conditions. These compounds could target pathways downstream of TPR, such as the cGAS-STING pathway or NF-κB signaling, to modulate the senescence-associated phenotype.

Gene therapy: Utilizing gene editing technologies to manipulate TPR expression or function in senescent cells could offer a targeted approach to alter nuclear organization and chromatin structure. By restoring or enhancing TPR activity, it may be possible to mitigate the effects of senescence and associated pathologies.

Combination therapies: Combining TPR-targeted interventions with existing senolytic therapies or other approaches targeting senescence could lead to synergistic effects and improved outcomes. By addressing multiple aspects of senescence, including nuclear architecture and inflammatory signaling, a combination therapy approach may offer enhanced therapeutic benefits.

What other nuclear pore components or nuclear envelope proteins might be involved in the regulation of cytoplasmic chromatin fragment formation and innate immune signaling during cellular senescence?

Several other nuclear pore components and nuclear envelope proteins may play a role in the regulation of cytoplasmic chromatin fragment formation and innate immune signaling during cellular senescence. Some potential candidates include:

NUP153: NUP153 is a key component of the nuclear pore complex and has been implicated in chromatin organization and gene regulation. It may interact with chromatin and transcription factors to modulate gene expression during senescence.

Lamin proteins: Lamin proteins are major components of the nuclear lamina and play a critical role in maintaining nuclear structure and integrity. Alterations in lamin expression or function have been linked to changes in chromatin organization and gene expression associated with senescence.

POM121: POM121 is a transmembrane nucleoporin that anchors the nuclear pore complex to the nuclear envelope. It may be involved in the regulation of nuclear-cytoplasmic transport and the maintenance of nuclear architecture during senescence.

Emerin: Emerin is an inner nuclear membrane protein that interacts with lamins and other nuclear envelope components. It has been implicated in chromatin organization and gene regulation, suggesting a potential role in senescence-associated changes in nuclear structure.

SUN proteins: SUN proteins are nuclear envelope proteins that interact with lamins and other nuclear components to maintain nuclear architecture. They may contribute to the regulation of chromatin dynamics and gene expression during senescence.

Exploring the roles of these nuclear pore components and nuclear envelope proteins in cytoplasmic chromatin fragment formation and innate immune signaling during senescence could provide valuable insights into the mechanisms underlying senescence-associated pathologies.

Could the insights from this study on the links between nuclear architecture, chromatin structure, and inflammatory signaling be extended to other cellular stress responses or age-related diseases beyond senescence?

The insights gained from studying the links between nuclear architecture, chromatin structure, and inflammatory signaling during senescence have broader implications for understanding cellular stress responses and age-related diseases beyond senescence. Several key points can be considered:

Cellular stress responses: The mechanisms identified in this study, such as the formation of cytoplasmic chromatin fragments and the activation of innate immune signaling pathways, may be relevant to other cellular stress responses, such as DNA damage, oxidative stress, and proteotoxic stress. Understanding how nuclear architecture and chromatin dynamics influence stress-induced signaling pathways could provide insights into the pathogenesis of various stress-related conditions.

Age-related diseases: Age-related diseases, including neurodegenerative disorders, cardiovascular diseases, and metabolic syndromes, are characterized by chronic inflammation and altered chromatin structure. The dysregulation of nuclear architecture and chromatin organization may contribute to the development and progression of age-related pathologies. Insights from studies on senescence could be applied to investigate the role of nuclear components in age-related diseases.

Therapeutic implications: Targeting nuclear pore components and nuclear envelope proteins involved in chromatin dynamics and inflammatory signaling pathways could have therapeutic implications for a wide range of diseases beyond senescence. Modulating these pathways to restore normal nuclear function and gene expression patterns may offer new therapeutic strategies for age-related conditions.

By extending the findings from studies on senescence to other cellular stress responses and age-related diseases, researchers can uncover common mechanisms underlying these conditions and identify potential targets for therapeutic interventions.