Periodic Reporting for period 1 - AUTO-SELECT (Dissect cargo selectivity in autophagy)
Okres sprawozdawczy: 2023-01-01 do 2025-06-30
The AUTO-SELECT project aims to uncover the principles of cargo selectivity in autophagy — a crucial cellular process for maintaining energy balance and quality control by degrading unwanted or damaged components. While bulk autophagy is traditionally viewed as a non-selective mechanism activated during starvation, emerging evidence suggests a more sophisticated, tissue-specific selectivity at play. AUTO-SELECT seeks to systematically define how different tissues target specific cargo for degradation, identify the molecular signals governing this selectivity, and harness these insights to develop therapeutic strategies for ER-storage diseases, such as Osteogenesis Imperfecta and Ehlers-Danlos Syndrome. By bridging the gap between energy metabolism and cellular clearance processes, this project has the potential to reshape our understanding of autophagy’s role in health and disease, offering new avenues for treating conditions linked to dysfunctional cellular clearance.
During the AUTO-SELECT project, significant progress was made in elucidating the mechanisms governing cargo selectivity in autophagy, particularly focusing on endoplasmic reticulum (ER) turnover. A pivotal discovery was identifying the role of FAM134C, an ER-phagy receptor, in mediating selective ER degradation during nutrient deprivation. The research demonstrated that under normal conditions, casein kinase 2 (CK2) phosphorylates FAM134C at specific residues near its LC3-interacting region, reducing its affinity for autophagy-related proteins and thus inhibiting ER-phagy. Upon starvation, inhibition of mTORC1 signaling decreases this phosphorylation, thereby activating FAM134C and promoting ER-phagy. This mechanism was validated both in vitro and in vivo, with FAM134C knockout models revealing its critical role in regulating liver lipid metabolism during fasting. These findings enhance our understanding of autophagy's selectivity and its implications for metabolic health.
Building upon the AUTO-SELECT project's exploration of autophagy's cargo selectivity, recent research has unveiled a critical pathway by which cells manage misfolded protein accumulation within the endoplasmic reticulum (ER). This study highlights the role of SESTRIN2, a nutrient sensor that, upon activation by the ER stress sensor XBP1, inhibits mTORC1 signaling. This inhibition facilitates the nuclear translocation of transcription factors TFEB and TFE3, which subsequently upregulate the expression of the ER-phagy receptor FAM134B and lysosomal genes. The enhanced expression of FAM134B promotes the formation of a FAM134B-Calnexin complex, facilitating the selective degradation of misfolded proteins via ER-phagy. Notably, pharmacological activation of FAM134B has been shown to improve the clearance of these aberrant proteins, suggesting potential therapeutic avenues for ER storage disorders.
Building upon the AUTO-SELECT project's exploration of autophagy's cargo selectivity, recent research has unveiled a critical pathway by which cells manage misfolded protein accumulation within the endoplasmic reticulum (ER). This study highlights the role of SESTRIN2, a nutrient sensor that, upon activation by the ER stress sensor XBP1, inhibits mTORC1 signaling. This inhibition facilitates the nuclear translocation of transcription factors TFEB and TFE3, which subsequently upregulate the expression of the ER-phagy receptor FAM134B and lysosomal genes. The enhanced expression of FAM134B promotes the formation of a FAM134B-Calnexin complex, facilitating the selective degradation of misfolded proteins via ER-phagy. Notably, pharmacological activation of FAM134B has been shown to improve the clearance of these aberrant proteins, suggesting potential therapeutic avenues for ER storage disorders.
The AUTO-SELECT project has significantly advanced our understanding of autophagy, particularly in the selective degradation of endoplasmic reticulum (ER) components, known as ER-phagy. A notable achievement is the elucidation of the activation mechanism of the FAM134B-Calnexin complex in the autophagic clearance of misfolded procollagen, highlighting a critical quality control mechanism within the ER. This discovery underscores the importance of selective autophagy in maintaining cellular homeostasis and offers potential therapeutic avenues for diseases associated with protein misfolding.
To translate these scientific insights into clinical applications, further research is necessary to identify and develop pharmacological agents that can modulate the FAM134B-Calnexin pathway effectively. Preclinical studies and clinical trials will be essential to assess the safety and efficacy of such interventions. Collaborations with pharmaceutical companies and securing intellectual property rights will facilitate the development and commercialization of these potential therapies. Additionally, engaging with regulatory bodies early in the development process will help navigate the path toward clinical approval, ensuring that new treatments reach patients suffering from ER storage disorders and related conditions.
In summary, the AUTO-SELECT project has not only deepened our comprehension of selective autophagy mechanisms but also paved the way for innovative therapeutic strategies targeting ER-associated pathologies.
To translate these scientific insights into clinical applications, further research is necessary to identify and develop pharmacological agents that can modulate the FAM134B-Calnexin pathway effectively. Preclinical studies and clinical trials will be essential to assess the safety and efficacy of such interventions. Collaborations with pharmaceutical companies and securing intellectual property rights will facilitate the development and commercialization of these potential therapies. Additionally, engaging with regulatory bodies early in the development process will help navigate the path toward clinical approval, ensuring that new treatments reach patients suffering from ER storage disorders and related conditions.
In summary, the AUTO-SELECT project has not only deepened our comprehension of selective autophagy mechanisms but also paved the way for innovative therapeutic strategies targeting ER-associated pathologies.