Regnase-1 and Regnase-3 Cooperatively Regulate Mast Cell Survival, Cytokine Expression, and Inflammatory Responses

Core Concepts

Regnase-1 and Regnase-3 cooperatively regulate mast cell survival, cytokine expression, and inflammatory responses, with Regnase-1 being crucial for maintaining mast cell homeostasis and Regnase-3 acting as a negative regulator of Regnase-1 expression.

Abstract

The content describes the role of the Regnase family of RNA-binding proteins, specifically Regnase-1 and Regnase-3, in regulating mast cell functions. Key highlights:

Expression of Regnase-1 and Regnase-3 is highly induced upon acute stimulation of mast cells, suggesting their importance in modulating mast cell responses.

Depletion of Regnase-1, alone or in combination with Regnase-3, leads to increased expression of inflammatory transcripts, including Tnf, in activated mast cells. Regnase-3 primarily acts by restraining Regnase-1 expression.

Regnase-1 is crucial for maintaining mast cell proliferation and survival, while Regnase-3 plays a more selective role in regulating inflammatory responses. Deletion of Regnase-1 leads to widespread transcriptome changes associated with cell cycle defects and metabolic dysregulation.

Regnase-3 physically interacts with Regnase-1 and is required to destabilize the Regnase-1 transcript, thereby negatively regulating its expression. This cross-regulation between the two Regnase proteins is important for their cooperative control of mast cell homeostasis and inflammatory responses.

Stats

Regnase-1 and Regnase-3 depletion led to significant upregulation of inflammatory transcripts, including Tnf, Il1b, Il2, and Nfkbiz.
Deletion of Regnase-1 resulted in increased basal expression of Tnf.
Regnase-1 deletion led to downregulation of genes involved in lipid and glucose metabolism, as well as cell cycle and DNA replication.

Quotes

"Regnase-1 is crucial to maintain basic cell proliferation and survival, while both Regnase-1 and −3 cooperatively regulate the expression of inflammatory transcripts upon mast cell activation, with Tnf being a primary target of both proteins."
"In mast cells, Regnase-3 directly interacts with Regnase-1 and is necessary to restrain Regnase-1 expression through the destabilization of its transcript."

Key Insights Distilled From

Crosstalk between the RNA-binding proteins Regnase-1 and -3 shapes mast cell survival and cytokine expression

by Bataclan,M.,... at www.biorxiv.org 01-28-2024

https://www.biorxiv.org/content/10.1101/2024.01.24.577016v1

Deeper Inquiries

How do the distinct subcellular localizations of Regnase-1 and Regnase-3 contribute to their unique and overlapping functions in mast cells

The distinct subcellular localizations of Regnase-1 and Regnase-3 play a crucial role in their unique and overlapping functions in mast cells. Regnase-1 and Regnase-3 were found to be localized within punctuated structures in the cytoplasm of activated mast cells, with limited overlap. This subcellular localization likely reflects their specific roles and interactions within the cell. Regnase-1 is primarily linked to the regulation of resting-state transcripts, while Regnase-3 exhibits a larger magnitude of induction upon activation, suggesting a role in modulating stimulus-induced inflammatory transcripts. The limited co-localization of Regnase-1 and Regnase-3 indicates that they may have distinct functions within the cell, with only a small proportion available for direct interaction. The interaction between Regnase-1 and Regnase-3, as well as their unique protein interactors, may contribute to their cooperative regulation of common targets, such as the inflammatory cytokine TNF. Overall, the subcellular localization of these proteins influences their regulatory functions and interplay in mast cells.

What are the potential therapeutic implications of targeting the Regnase-1/Regnase-3 axis in the context of mast cell-driven diseases, such as allergies and anaphylaxis

Targeting the Regnase-1/Regnase-3 axis in mast cell-driven diseases, such as allergies and anaphylaxis, holds significant therapeutic implications. The study revealed that Regnase-1 and Regnase-3 play crucial roles in modulating mast cell responses, including the regulation of inflammatory gene expression and homeostatic functions. In diseases characterized by mast cell hyperactivation, such as allergies and anaphylaxis, dysregulation of inflammatory responses can lead to harmful outcomes. By targeting the Regnase-1/Regnase-3 axis, it may be possible to modulate mast cell activation and cytokine production, potentially mitigating the excessive inflammatory responses seen in these conditions. Therapeutic interventions aimed at enhancing the regulatory functions of Regnase-1 and Regnase-3 could help restore the balance in mast cell functionality, leading to improved management of allergic reactions and anaphylaxis. Further research into the specific mechanisms of action and potential drug targets within the Regnase-1/Regnase-3 axis is warranted to explore the full therapeutic potential in mast cell-driven diseases.

Given the role of Regnase-1 in regulating metabolic processes, how might this contribute to the maintenance of mast cell homeostasis and function

The role of Regnase-1 in regulating metabolic processes can significantly contribute to the maintenance of mast cell homeostasis and function. The study revealed that Regnase-1 deletion led to widespread transcriptome changes associated with cell cycle defects, DNA replication, and metabolic processes, including lipid and glucose metabolism. These findings suggest that Regnase-1 plays a critical role in regulating metabolic pathways required for cell maintenance and survival. Dysregulation of lipid and glucose metabolism, as observed in mast cells lacking Regnase-1, can impact cellular fitness, proliferation, and overall functionality. The involvement of Regnase-1 in maintaining mast cell survival and proliferation underscores the importance of metabolic regulation in mast cell homeostasis. Targeting the metabolic pathways regulated by Regnase-1 could offer novel therapeutic strategies for modulating mast cell function and potentially managing mast cell-driven diseases. Further research into the specific metabolic pathways influenced by Regnase-1 in mast cells is essential for a comprehensive understanding of its role in maintaining cellular homeostasis.