näkemys - Biology - # Collagen-I Fibrillogenesis

The Role of Endosome in Collagen Fibril Assembly

Q: How does the circadian regulation impact the efficiency of endocytic recycling in different cell types?

The circadian regulation plays a crucial role in modulating the efficiency of endocytic recycling in various cell types. In this study, it was observed that collagen-I endocytosis is under circadian control, with rhythmic fluctuations in collagen uptake by synchronized fibroblasts over time. The periodicity of collagen-I uptake was approximately 23.8 hours, indicating a cyclic pattern influenced by the circadian clock. This rhythmic process ensures that cells take up exogenous collagen at specific times and then recycle it into fibrils for assembly. Interestingly, there was an inverse correlation between peak uptake times and fibril numbers, suggesting a coordinated mechanism where cells endocytose collagen during specific phases to prepare for efficient fibril formation later on. Overall, the circadian regulation optimizes the timing of endocytic processes such as collagen uptake and recycling, ensuring that cells can efficiently utilize extracellular resources for fibrillogenesis based on their internal biological clock.

Q: Could other proteins be involved in the regulation of collagen homeostasis apart from VPS33B and integrin α11?

While VPS33B and integrin α11 play key roles in regulating collagen homeostasis through their involvement in endosomal trafficking and fibrillogenesis, there are likely other proteins contributing to this complex process. One potential group of proteins could be additional components of the endocytic machinery involved in sorting and transporting collagens within cells. Proteins responsible for vesicle formation or fusion may also influence how collagens are recycled or targeted towards assembly sites. Moreover, enzymes involved in post-translational modifications of collagens (such as prolyl hydroxylases) could impact their stability or interactions with binding partners like integrins. Signaling molecules that regulate gene expression related to ECM remodeling might also have indirect effects on collagen homeostasis. Furthermore, regulatory factors controlling cytoskeletal dynamics or cellular adhesion could influence how cells interact with collagens during assembly processes. Therefore, while VPS33B and integrin α11 are critical players identified here, exploring a broader network of proteins associated with ECM turnover may reveal additional regulators impacting collagen homeostasis.

Q: How can understanding the role of endosomes in fibrosis lead to potential therapeutic interventions beyond traditional treatments?

Understanding the pivotal role played by endosomes - particularly through molecules like VPS33B - offers new avenues for therapeutic interventions targeting fibrotic diseases beyond conventional approaches: Targeted Drug Development: By identifying key players like VPS33B involved specifically in aberrant ECM remodeling seen in fibrosis conditions such as IPF or chronic wounds; researchers can develop drugs targeting these molecules directly to disrupt pathological pathways leading to excessive deposition of collagens. Precision Medicine: Utilizing knowledge about molecular mechanisms involving endosomal trafficking allows for personalized treatment strategies tailored to individual patients based on variations seen at these levels which contribute significantly to disease progression. Novel Therapeutic Targets: Identification of novel targets within intracellular pathways opens doors for developing innovative therapies focusing not only on symptom management but addressing root causes at a cellular level. Combination Therapies: Insights into multiple protein interactions influencing ECM dynamics provide opportunities for combination therapies targeting different points along these pathways simultaneously - potentially enhancing treatment efficacy compared to single-target approaches. 5 .Early Intervention Strategies: Understanding early changes occurring at subcellular levels due to dysregulated signaling cascades enables clinicians to intervene before irreversible damage occurs; paving way for preventive measures rather than just symptomatic relief. By delving deeper into how cellular processes involving endosomes contribute towards fibrotic conditions like IPF or chronic skin wounds; researchers can uncover novel targets offering hope for more effective treatments addressing underlying pathophysiology rather than just managing symptoms typically associated with current standard care protocols

Keskeiset käsitteet

Circadian-regulated endocytic recycling is crucial for collagen fibril assembly, involving VPS33B and integrin α11 subunit.

Tiivistelmä

Abstract:
- Collagen-I fibrillogenesis is essential for health and development.
- Endocytic system recycles collagen-I for new fibrils.
Introduction:
- Unclear mechanisms of collagen fibril formation.
- Cell surface-mediated fibrillogenesis involves integrins.
Data Extraction:
- Cells recycle exogenous collagen-I into new fibrils.
- Inhibition of endocytosis reduces collagen fibril assembly.
Results:
- VPS33B knockout leads to fewer collagen fibrils.
- Overexpression of VPS33B increases collagen fibrils but disrupts rhythmicity.
VPS33B Localization:
- VPS33B co-traffics with collagen-I in vesicular structures.
Integrin α11 Subunit:
- Integrin α11 mediates VPS33B-dependent fibrillogenesis.
IPF Study:
- IPF fibroblasts show elevated levels of VPS33B and integrin α11 subunit.
Chronic Skin Wounds:
- Integrin α11 and VPS33B are elevated in chronic skin wounds.

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biorxiv.org

Tilastot

Cells utilize endocytic recycling to assemble new fibrils even without endogenous collagen production.
Inhibition of clathrin-mediated endocytosis reduces collagen-I secretion and impacts fibrillogenesis.
VPSko cells have fewer collagen fibrils, while VPSoe cells show continuous deposition of collagen-I.

Lainaukset

"Endocytic recycling of exogenous collagen is central to homeostatic assembly."
"Inhibiting endocytosis affects both secretion and assembly of soluble collagen protomers."

Tärkeimmät oivallukset

Endocytic recycling is central to circadian collagen fibrillogenesis and disrupted in fibrosis

by CHANG,J., PI... klo www.biorxiv.org 03-25-2021

https://www.biorxiv.org/content/10.1101/2021.03.25.436925v3

Syvällisempiä Kysymyksiä

How does the circadian regulation impact the efficiency of endocytic recycling in different cell types?

The circadian regulation plays a crucial role in modulating the efficiency of endocytic recycling in various cell types. In this study, it was observed that collagen-I endocytosis is under circadian control, with rhythmic fluctuations in collagen uptake by synchronized fibroblasts over time. The periodicity of collagen-I uptake was approximately 23.8 hours, indicating a cyclic pattern influenced by the circadian clock.
This rhythmic process ensures that cells take up exogenous collagen at specific times and then recycle it into fibrils for assembly. Interestingly, there was an inverse correlation between peak uptake times and fibril numbers, suggesting a coordinated mechanism where cells endocytose collagen during specific phases to prepare for efficient fibril formation later on.
Overall, the circadian regulation optimizes the timing of endocytic processes such as collagen uptake and recycling, ensuring that cells can efficiently utilize extracellular resources for fibrillogenesis based on their internal biological clock.

Could other proteins be involved in the regulation of collagen homeostasis apart from VPS33B and integrin α11?

While VPS33B and integrin α11 play key roles in regulating collagen homeostasis through their involvement in endosomal trafficking and fibrillogenesis, there are likely other proteins contributing to this complex process.
One potential group of proteins could be additional components of the endocytic machinery involved in sorting and transporting collagens within cells. Proteins responsible for vesicle formation or fusion may also influence how collagens are recycled or targeted towards assembly sites.
Moreover, enzymes involved in post-translational modifications of collagens (such as prolyl hydroxylases) could impact their stability or interactions with binding partners like integrins. Signaling molecules that regulate gene expression related to ECM remodeling might also have indirect effects on collagen homeostasis.
Furthermore, regulatory factors controlling cytoskeletal dynamics or cellular adhesion could influence how cells interact with collagens during assembly processes. Therefore, while VPS33B and integrin α11 are critical players identified here, exploring a broader network of proteins associated with ECM turnover may reveal additional regulators impacting collagen homeostasis.

How can understanding the role of endosomes in fibrosis lead to potential therapeutic interventions beyond traditional treatments?

Understanding the pivotal role played by endosomes - particularly through molecules like VPS33B - offers new avenues for therapeutic interventions targeting fibrotic diseases beyond conventional approaches:

Targeted Drug Development: By identifying key players like VPS33B involved specifically in aberrant ECM remodeling seen in fibrosis conditions such as IPF or chronic wounds; researchers can develop drugs targeting these molecules directly to disrupt pathological pathways leading to excessive deposition of collagens.

Precision Medicine: Utilizing knowledge about molecular mechanisms involving endosomal trafficking allows for personalized treatment strategies tailored to individual patients based on variations seen at these levels which contribute significantly to disease progression.

Novel Therapeutic Targets: Identification of novel targets within intracellular pathways opens doors for developing innovative therapies focusing not only on symptom management but addressing root causes at a cellular level.

Combination Therapies: Insights into multiple protein interactions influencing ECM dynamics provide opportunities for combination therapies targeting different points along these pathways simultaneously - potentially enhancing treatment efficacy compared to single-target approaches.

5 .Early Intervention Strategies: Understanding early changes occurring at subcellular levels due to dysregulated signaling cascades enables clinicians to intervene before irreversible damage occurs; paving way for preventive measures rather than just symptomatic relief.
By delving deeper into how cellular processes involving endosomes contribute towards fibrotic conditions like IPF or chronic skin wounds; researchers can uncover novel targets offering hope for more effective treatments addressing underlying pathophysiology rather than just managing symptoms typically associated with current standard care protocols