spostrzeżenie - Molecular Biology - # Interferon-induced PARP14-mediated ADP-ribosylation in p62 bodies

Interferon-Induced PARP14-Mediated ADP-Ribosylation Regulates the Formation of Distinct p62 Bodies

Q: What are the specific ubiquitinated protein substrates that are targeted for proteasomal degradation within these IFNγ-induced ADPr-enriched p62 bodies, and how does this regulation contribute to the cellular response to interferon?

Within the IFNγ-induced ADPr-enriched p62 bodies, the specific ubiquitinated protein substrates targeted for proteasomal degradation are likely proteins involved in immune signaling and protein quality control. These substrates could include misfolded or damaged proteins, signaling molecules involved in NF-κB and NRF2 pathways, and potentially viral proteins targeted for degradation. The presence of K48-linked and K63-linked polyubiquitin chains within these p62 bodies suggests a diverse range of substrates marked for proteasomal degradation. The regulation of these ubiquitinated protein substrates within the p62 bodies contributes to the cellular response to interferon by facilitating the clearance of damaged or unwanted proteins, regulating immune signaling pathways, and potentially targeting viral components for degradation. By sequestering these ubiquitinated substrates within the p62 bodies, the cell can efficiently direct them towards the proteasome for degradation, thereby maintaining cellular homeostasis and modulating the immune response to interferon.

Q: How does the balance between PARP14's transferase and hydrolase activities get modulated within the context of these p62 bodies, and what are the potential mechanisms by which the ubiquitin-proteasome system regulates this balance?

The balance between PARP14's transferase and hydrolase activities within the p62 bodies is likely modulated by the availability of substrates for ADP-ribosylation and de-ribosylation. In the context of these p62 bodies, the increased levels of PARP14 and the presence of specific substrates may favor its transferase activity, leading to the addition of ADP-ribose moieties onto target proteins. This ADP-ribosylation process can be reversed by the hydrolase activity of PARP14, maintaining a dynamic equilibrium of ADP-ribosylation and de-ribosylation within the condensates. The ubiquitin-proteasome system regulates this balance by influencing the turnover of PARP14 and potentially other regulatory proteins involved in ADP-ribosylation. Proteasomal degradation of PARP14 or its interacting partners could impact the availability of substrates for ADP-ribosylation, thereby modulating the balance between transferase and hydrolase activities. Additionally, the ubiquitin-proteasome system may target specific proteins that regulate PARP14 activity, such as E3 ligases or deubiquitinases, to fine-tune the ADP-ribosylation dynamics within the p62 bodies.

Q: Given the potential role of these IFNγ-induced ADPr-containing p62 bodies in viral infection and immunotherapy resistance, what are the broader physiological and pathological implications of understanding their composition and regulation?

Understanding the composition and regulation of IFNγ-induced ADPr-containing p62 bodies has significant physiological and pathological implications. In the context of viral infection, these condensates may play a role in modulating the host immune response by regulating the degradation of viral components and influencing immune signaling pathways. By targeting specific substrates for proteasomal degradation, these p62 bodies could impact viral replication, host defense mechanisms, and the overall outcome of viral infections. In the context of immunotherapy resistance, the dysregulation of ADP-ribosylation within p62 bodies could contribute to the evasion of immune surveillance and resistance to therapeutic interventions. Targeting the components and regulatory mechanisms of these condensates could provide novel therapeutic strategies for overcoming immunotherapy resistance and enhancing the efficacy of immune-based treatments. Overall, a comprehensive understanding of the composition and regulation of IFNγ-induced ADPr-containing p62 bodies can shed light on their roles in viral infections, immune responses, and disease pathogenesis, offering potential targets for therapeutic intervention and disease management.

Główne pojęcia

Interferon-induced transcriptional activation of PARP14 leads to the formation of ADP-ribosylated p62 bodies, which require an active ubiquitin-proteasome system but are independent of autophagy.

Streszczenie

The study investigates the molecular mechanisms behind the formation of interferon-induced ADP-ribosylation (ADPr) condensates in the cytoplasm. The key findings are:

Interferon-γ (IFNγ) treatment transcriptionally activates PARP14, a mono-ADP-ribosyltransferase, leading to the formation of ADPr condensates.
The physical presence and catalytic activity of PARP14 are both essential for the formation of these ADPr condensates.
The ADPr condensates colocalize with the selective autophagy receptor p62 and its binding partner NBR1, as well as K48- and K63-linked polyubiquitin chains, but lack the autophagosome marker LC3B.
Knockdown of p62 disrupts the formation of these ADPr condensates, indicating that p62 is required for their condensation.
The formation of these ADPr-enriched p62 bodies depends on an active ubiquitin-proteasome system, but not on autophagy.
PARP14-mediated ADP-ribosylation of p62 facilitates the co-condensation of PARP14, ADPr, and p62.
The ubiquitin-proteasome system is required for the condensation of PARP14 and ADPr in p62 bodies, potentially by regulating the balance between PARP14's transferase and hydrolase activities.

These findings demonstrate that interferon triggers the formation of a distinct class of p62 bodies enriched with PARP14-mediated ADP-ribosylation, which requires an active ubiquitin-proteasome system.

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biorxiv.org

Statystyki

IFNγ treatment leads to a significant upregulation of PARP14 mRNA and protein levels in A549 cells.
Knockdown or genetic depletion of PARP14 abolishes the formation of IFNγ-induced ADPr condensates.
Inhibition of PARP14's catalytic activity using specific inhibitors, such as ITK7 and RBN012579, prevents the formation of ADPr condensates.
IFNγ treatment increases the mobile fraction of p62 within the bodies, but does not alter the exchange dynamics between p62 bodies and the cytoplasm.
Inhibition of the ubiquitin-activating enzyme E1 (using TAK-243) or the proteasome (using MG132, Epoxomicin) disrupts the formation of ADPr condensates without affecting p62 and PARP14 protein levels.

Cytaty

"Interferon-induced ADPr colocalizes with PARP14, and these PARP14/ADPr condensates contain key components of p62 bodies—including the selective autophagy receptor p62 and its binding partner NBR1, along with K48-linked and K63-linked polyubiquitin chains—but lack the autophagosome marker LC3B."
"Knockdown of p62 disrupts the formation of these ADPr condensates. Importantly, these structures are unaffected by autophagy inhibition but depend on both ubiquitin activation and proteasome activity."

Kluczowe wnioski z

Interferon-Induced PARP14-Mediated ADP-Ribosylation in p62 Bodies Requires an Active Ubiquitin-Proteasome System

by Raja,R., Bis... o www.biorxiv.org 05-24-2024

https://www.biorxiv.org/content/10.1101/2024.05.22.595402v1

Głębsze pytania

What are the specific ubiquitinated protein substrates that are targeted for proteasomal degradation within these IFNγ-induced ADPr-enriched p62 bodies, and how does this regulation contribute to the cellular response to interferon?

Within the IFNγ-induced ADPr-enriched p62 bodies, the specific ubiquitinated protein substrates targeted for proteasomal degradation are likely proteins involved in immune signaling and protein quality control. These substrates could include misfolded or damaged proteins, signaling molecules involved in NF-κB and NRF2 pathways, and potentially viral proteins targeted for degradation. The presence of K48-linked and K63-linked polyubiquitin chains within these p62 bodies suggests a diverse range of substrates marked for proteasomal degradation.
The regulation of these ubiquitinated protein substrates within the p62 bodies contributes to the cellular response to interferon by facilitating the clearance of damaged or unwanted proteins, regulating immune signaling pathways, and potentially targeting viral components for degradation. By sequestering these ubiquitinated substrates within the p62 bodies, the cell can efficiently direct them towards the proteasome for degradation, thereby maintaining cellular homeostasis and modulating the immune response to interferon.

How does the balance between PARP14's transferase and hydrolase activities get modulated within the context of these p62 bodies, and what are the potential mechanisms by which the ubiquitin-proteasome system regulates this balance?

The balance between PARP14's transferase and hydrolase activities within the p62 bodies is likely modulated by the availability of substrates for ADP-ribosylation and de-ribosylation. In the context of these p62 bodies, the increased levels of PARP14 and the presence of specific substrates may favor its transferase activity, leading to the addition of ADP-ribose moieties onto target proteins. This ADP-ribosylation process can be reversed by the hydrolase activity of PARP14, maintaining a dynamic equilibrium of ADP-ribosylation and de-ribosylation within the condensates.
The ubiquitin-proteasome system regulates this balance by influencing the turnover of PARP14 and potentially other regulatory proteins involved in ADP-ribosylation. Proteasomal degradation of PARP14 or its interacting partners could impact the availability of substrates for ADP-ribosylation, thereby modulating the balance between transferase and hydrolase activities. Additionally, the ubiquitin-proteasome system may target specific proteins that regulate PARP14 activity, such as E3 ligases or deubiquitinases, to fine-tune the ADP-ribosylation dynamics within the p62 bodies.

Given the potential role of these IFNγ-induced ADPr-containing p62 bodies in viral infection and immunotherapy resistance, what are the broader physiological and pathological implications of understanding their composition and regulation?

Understanding the composition and regulation of IFNγ-induced ADPr-containing p62 bodies has significant physiological and pathological implications. In the context of viral infection, these condensates may play a role in modulating the host immune response by regulating the degradation of viral components and influencing immune signaling pathways. By targeting specific substrates for proteasomal degradation, these p62 bodies could impact viral replication, host defense mechanisms, and the overall outcome of viral infections.
In the context of immunotherapy resistance, the dysregulation of ADP-ribosylation within p62 bodies could contribute to the evasion of immune surveillance and resistance to therapeutic interventions. Targeting the components and regulatory mechanisms of these condensates could provide novel therapeutic strategies for overcoming immunotherapy resistance and enhancing the efficacy of immune-based treatments.
Overall, a comprehensive understanding of the composition and regulation of IFNγ-induced ADPr-containing p62 bodies can shed light on their roles in viral infections, immune responses, and disease pathogenesis, offering potential targets for therapeutic intervention and disease management.