Harnessing Protein Transport Coupling to Achieve Targeted Protein Relocalization for Therapeutic Potential

מושגי ליבה

Subcellular protein localization can be modulated through molecular coupling to shuttle proteins, enabling the rewiring of the interactome to address disease-driving phenotypes.

תקציר

The article discusses the concept of targeted protein relocalization as a potential therapeutic approach for diseases such as cancer and neurodegenerative disorders. Subcellular protein localization is crucial for regulating protein function, and its disruption can contribute to disease pathogenesis.

The authors identify a collection of shuttle proteins with potent ligands that can be incorporated into targeted relocalization-activating molecules (TRAMs). These TRAMs can be used to relocalize endogenous proteins by coupling them to the trafficking of the shuttle proteins. The authors demonstrate the feasibility of this approach by modulating the steady-state localization of various proteins, including disease-driving mutant proteins such as SMARCB1Q318X, TDP43ΔNLS, and FUSR495X.

The article highlights the use of nuclear hormone receptors as shuttles to redistribute the disease-driving mutant proteins. The TRAM-mediated relocalization of FUSR495X to the nucleus from the cytoplasm was found to correlate with a reduction in the number of stress granules in a model of cellular stress.

The authors also demonstrate the relocalization of endogenous proteins, such as PRMT9, SOS1, and FKBP12, using methionyl aminopeptidase 2 and poly(ADP-ribose) polymerase 1 as endogenous cytoplasmic and nuclear shuttles, respectively.

Furthermore, the article discusses the potential of small-molecule-mediated redistribution of nicotinamide nucleotide adenylyltransferase 1 from nuclei to axons in primary neurons, which was able to slow axonal degeneration and pharmacologically mimic the genetic WldS gain-of-function phenotype in mice resistant to certain types of neurodegeneration.

The concept of targeted protein relocalization could inspire new approaches for treating diseases through interactome rewiring, offering a promising avenue for therapeutic development.

סטטיסטיקה

Subcellular protein localization regulates protein function and can be corrupted in cancers and neurodegenerative diseases.
Targeted protein relocalization could be an attractive approach for addressing disease-driving phenotypes.
TRAM-mediated relocalization of FUSR495X to the nucleus from the cytoplasm correlated with a reduction in the number of stress granules in a model of cellular stress.
Small-molecule-mediated redistribution of nicotinamide nucleotide adenylyltransferase 1 from nuclei to axons in primary neurons was able to slow axonal degeneration and pharmacologically mimic the genetic WldS gain-of-function phenotype in mice resistant to certain types of neurodegeneration.

ציטוטים

"Molecules that harness the trafficking of a shuttle protein to control the subcellular localization of a target protein could enforce targeted protein relocalization and rewire the interactome."
"The concept of targeted protein relocalization could therefore inspire approaches for treating disease through interactome rewiring."

תובנות מפתח מזוקקות מ:

Targeted protein relocalization via protein transport coupling - Nature

by Christine S.... ב- www.nature.com 09-18-2024

https://www.nature.com/articles/s41586-024-07950-8

שאלות מעמיקות

How can the TRAM-mediated relocalization approach be further optimized to enhance its therapeutic potential?

To enhance the therapeutic potential of the TRAM-mediated relocalization approach, several strategies can be considered. First, optimizing the specificity and affinity of the shuttle proteins used in TRAMs is crucial. This can be achieved by engineering shuttle proteins with enhanced localization sequences that are more effective in guiding target proteins to desired subcellular compartments. Additionally, the development of more potent ligands that can bind to shuttle proteins with higher affinity may improve the efficiency of relocalization.
Second, incorporating advanced delivery systems, such as nanoparticles or liposomes, could facilitate the targeted delivery of TRAMs to specific tissues or cell types, thereby increasing the local concentration of the therapeutic agents and minimizing off-target effects.
Third, exploring combinatorial approaches that integrate TRAMs with other therapeutic modalities, such as gene editing or immunotherapy, could provide synergistic effects and enhance the overall efficacy of treatment. For instance, combining TRAMs with CRISPR/Cas9 technology could allow for precise modifications of the interactome alongside relocalization.
Finally, extensive in vivo studies and clinical trials are necessary to assess the long-term effects and safety profiles of TRAMs, as well as to refine dosing regimens and administration routes to maximize therapeutic outcomes.

What are the potential limitations or challenges in translating this concept from in vitro and animal models to clinical applications?

Translating the TRAM-mediated relocalization concept from in vitro and animal models to clinical applications presents several challenges. One significant limitation is the complexity of human biology compared to model organisms. The interactions and pathways involved in protein localization and function may differ significantly in humans, potentially affecting the efficacy of TRAMs.
Another challenge is the potential for off-target effects. While TRAMs are designed to specifically relocalize target proteins, unintended interactions with other cellular components could lead to adverse effects or toxicity. Rigorous testing is required to ensure that TRAMs do not disrupt essential cellular processes.
Additionally, the delivery of TRAMs to specific tissues or cells in humans poses a logistical challenge. Achieving effective and targeted delivery while avoiding systemic exposure is critical for minimizing side effects and maximizing therapeutic efficacy.
Finally, regulatory hurdles must be navigated, as the development of novel therapeutic agents often requires extensive preclinical and clinical testing to demonstrate safety and efficacy. This process can be time-consuming and costly, potentially delaying the availability of TRAM-based therapies for patients.

What other cellular processes or pathways could be targeted to achieve similar interactome rewiring for therapeutic purposes?

In addition to targeted protein relocalization, several other cellular processes and pathways could be targeted to achieve similar interactome rewiring for therapeutic purposes. One promising avenue is the modulation of protein-protein interactions (PPIs). By designing small molecules or peptides that can disrupt or enhance specific PPIs, it may be possible to alter signaling pathways and cellular responses associated with diseases such as cancer and neurodegeneration.
Another potential target is the regulation of post-translational modifications (PTMs), such as phosphorylation, ubiquitination, or acetylation. By developing inhibitors or activators of specific enzymes involved in PTMs, researchers could influence the stability, localization, and activity of proteins, thereby rewiring cellular networks.
Additionally, targeting cellular signaling pathways, such as the MAPK or PI3K/Akt pathways, could provide therapeutic benefits by restoring normal signaling in diseased cells. Modulating these pathways can influence cell growth, survival, and differentiation, making them attractive targets for drug development.
Finally, the manipulation of cellular stress responses, such as the unfolded protein response (UPR) or autophagy, could also be explored. By enhancing or inhibiting these pathways, it may be possible to alter the cellular environment and promote cell survival or death in a controlled manner, offering new strategies for treating diseases characterized by protein misfolding or aggregation.