Redox Signaling Regulates the Trafficking and Function of La Protein in Osteoclast Fusion and Bone Resorption

Core Concepts

Transient reactive oxygen species (ROS) signaling during osteoclast differentiation triggers a shift from reduced to oxidized species of La protein, promoting its trafficking from the nucleus to the cell surface where it regulates osteoclast fusion and bone resorptive function.

Abstract

The content discusses the role of redox signaling in regulating the localization and function of La protein during osteoclast formation and bone resorption. Key points: Osteoclast fusion and bone resorption are promoted by an oxidized species of cell surface-associated La protein, which is distinct from the reduced, nuclear form of La. Transient ROS signaling during osteoclast differentiation triggers the shift from reduced to oxidized La species, leading to La's dephosphorylation and delivery to the osteoclast surface. The oxidation of critical cysteine residues (Cys232 and Cys245) in the C-terminal half of La is required for its ability to promote osteoclast fusion and resorption. Suppressing ROS signaling with NAC inhibits the transition from reduced to oxidized La species, prevents La's surface delivery, and impairs osteoclast multinucleation. Exogenous addition of the C-terminal La fragment can rescue the fusion-inhibiting effects of NAT, but this rescue is dependent on the presence of the critical cysteine residues. The findings suggest that redox-dependent changes in La trafficking and function play a critical role in regulating osteoclast fusion and bone resorption, and represent a potential therapeutic target for skeletal disorders.

Stats

Transient ROS signaling is induced during RANKL-initiated osteoclast differentiation. Inhibition of ROS signaling with NAC suppresses the shift from reduced to oxidized La species in differentiating osteoclasts. Mutation of Cys232 and Cys245 in the C-terminal half of La abrogates its ability to promote osteoclast fusion. Exogenous addition of the wild-type C-terminal La fragment can rescue the fusion-inhibiting effects of NAC, but the cysteine mutant fragment cannot.

Quotes

"Transient, moderate increases in ROS levels, referred to as redox signaling 12,13 or a mild oxidative stress 14, play important roles in diverse cellular differentiation processes15-17." "Finding that the surface pool of La that manages osteoclast size and resorptive function is primarily composed of an oxidized La molecular species." "Our data, which indicate that fusion competence in osteoclast precursors depends on ROS signaling, can be, at least partially, explained by the oxidation-dependent changes in the structure of La protein and its nucleo-cytoplasmic-cell surface shuttling."

Key Insights Distilled From

Formation of multinucleated osteoclasts depends on an oxidized species of cell surface associated La protein

by Leikina,E., ... at www.biorxiv.org 05-05-2024

https://www.biorxiv.org/content/10.1101/2024.05.02.592254v1

Deeper Inquiries

What other cellular processes or signaling pathways might be regulated by the redox-dependent trafficking and function of La protein?

The redox-dependent trafficking and function of La protein may regulate various cellular processes and signaling pathways beyond osteoclast formation. One potential area of interest is in RNA metabolism and protein synthesis. La protein is known to play a crucial role in the maturation of RNA polymerase III transcripts, particularly tRNA. The redox-dependent regulation of La could impact the processing and maturation of these transcripts, influencing protein synthesis and overall cellular function. Additionally, the redox-dependent function of La may have implications in immune responses and inflammation. La protein has been implicated in the regulation of inflammatory responses, and its redox-dependent trafficking could modulate the expression of inflammatory mediators and cytokines. By influencing the stability and translation of specific mRNAs involved in immune responses, La protein may contribute to the regulation of the immune system. Furthermore, the redox-dependent regulation of La could intersect with pathways involved in cell proliferation and differentiation. By modulating the function of La through redox signaling, cells may fine-tune their responses to growth factors and differentiation cues, impacting processes such as cell cycle progression and tissue development.

How might the redox-dependent regulation of La be integrated with other known mechanisms controlling osteoclast formation and activity, such as transcriptional regulation or calcium signaling?

The redox-dependent regulation of La in osteoclasts could be integrated with other mechanisms controlling osteoclast formation and activity, such as transcriptional regulation and calcium signaling, to orchestrate the complex process of bone remodeling. Transcriptional Regulation: Transcription factors involved in osteoclast differentiation, such as NFATc1 and cFOS, could interact with the redox-regulated La protein to modulate gene expression during osteoclastogenesis. The redox state of La may influence its interaction with transcriptional regulators, impacting the expression of genes essential for osteoclast fusion and function. Calcium Signaling: Calcium signaling plays a critical role in osteoclast differentiation and bone resorption. The redox-dependent trafficking of La could intersect with calcium signaling pathways to coordinate osteoclast activity. Calcium-dependent signaling molecules may regulate the redox state of La, influencing its localization and function in osteoclasts. ROS Signaling: Reactive oxygen species (ROS) signaling, which triggers the redox-dependent changes in La, could crosstalk with other signaling pathways involved in osteoclast formation. ROS signaling may act upstream or downstream of La to regulate osteoclast fusion and resorptive function, forming a complex network of signaling interactions. By integrating the redox-dependent regulation of La with transcriptional control, calcium signaling, and ROS signaling, osteoclasts can fine-tune their response to environmental cues and maintain bone homeostasis.

Could the principles of redox-dependent protein trafficking and function uncovered for La be applied to understand the regulation of other moonlighting proteins involved in specialized cellular processes?

The principles of redox-dependent protein trafficking and function uncovered for La could indeed be applied to understand the regulation of other moonlighting proteins involved in specialized cellular processes. Moonlighting proteins, which perform multiple functions in different cellular contexts, often undergo conformational changes or post-translational modifications to switch between their different roles. Redox signaling can serve as a key regulator of these transitions, influencing the localization and activity of moonlighting proteins in response to cellular redox status. Structural Changes: Similar to La, other moonlighting proteins may undergo redox-dependent structural changes that alter their function and subcellular localization. Redox-sensitive cysteine residues or disulfide bond formation could modulate the conformation of moonlighting proteins, allowing them to switch between different functional states. Intracellular Trafficking: Redox signaling can impact the intracellular trafficking of moonlighting proteins, directing them to specific cellular compartments or organelles based on the redox environment. The redox-dependent regulation of protein trafficking could control the availability of moonlighting proteins at different subcellular locations, influencing their diverse functions. Functional Switching: Redox-dependent modifications may trigger functional switching in moonlighting proteins, enabling them to perform specialized roles in response to oxidative stress or redox changes. By understanding the redox regulation of moonlighting proteins, researchers can uncover novel mechanisms by which these proteins contribute to cellular processes. Overall, the principles of redox-dependent protein trafficking and function elucidated for La can serve as a paradigm for investigating the regulation of other moonlighting proteins and their roles in specialized cellular processes.