| Autor: |
Birnbaum, Susanna K., Cohen, Jennifer D., Belfi, Alexandra, Murray, John I., Adams, Jennifer R. G., Chisholm, Andrew D., Sundaram, Meera V. |
| Předmět: |
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| Zdroj: |
PLoS Genetics; 9/18/2023, Vol. 19 Issue 9, p1-26, 26p |
| Abstrakt: |
Some types of collagens, including transmembrane MACIT collagens and C. elegans cuticle collagens, are N-terminally cleaved at a dibasic site that resembles the consensus for furin or other proprotein convertases of the subtilisin/kexin (PCSK) family. Such cleavage may release transmembrane collagens from the plasma membrane and affect extracellular matrix assembly or structure. However, the functional consequences of such cleavage are unclear and evidence for the role of specific PCSKs is lacking. Here, we used endogenous collagen fusions to fluorescent proteins to visualize the secretion and assembly of the first collagen-based cuticle in C. elegans and then tested the role of the PCSK BLI-4 in these processes. Unexpectedly, we found that cuticle collagens SQT-3 and DPY-17 are secreted into the extraembryonic space several hours before cuticle matrix assembly. Furthermore, this early secretion depends on BLI-4/PCSK; in bli-4 and cleavage-site mutants, SQT-3 and DPY-17 are not efficiently secreted and instead form large intracellular puncta. Their later assembly into cuticle matrix is reduced but not entirely blocked. These data reveal a role for collagen N-terminal processing in intracellular trafficking and the control of matrix assembly in vivo. Our observations also prompt a revision of the classic model for C. elegans cuticle matrix assembly and the pre-cuticle-to-cuticle transition, suggesting that cuticle layer assembly proceeds via a series of regulated steps and not simply by sequential secretion and deposition. Author summary: Extracellular matrices coat cell surfaces to affect many aspects of animal biology. Collagens are among the most common constituents of such matrices and often form fibrillar- or mesh-like structures. It is important that these structures form only at the right time and place in the extracellular environment, and not prematurely during intracellular trafficking. Type I collagen matrix assembly typically occurs after proteolytic cleavage to remove both the N- and C-terminal ends of collagen molecules, and defects in this cleavage can cause a variety of human matrix disorders. Nevertheless, many questions remain about how N-terminal cleavage impacts collagen matrix assembly, particularly within other families of collagens that may be regulated differently than Type I collagen. The nematode Caenorhabditis elegans has an exoskeleton or cuticle that is composed of many collagens, and sequential secretion and membrane-proximal assembly of different collagens has been supposed to explain the eventual layered structure of the cuticle. Here we visualized tagged collagens during cuticle assembly and investigated the roles of N-terminal cleavage by characterizing mutants in the predicted collagen protease BLI-4 (a member of the furin/PCSK family) and also mutants in the predicted N-terminal cleavage sites within the tagged cuticle collagens. We observed that collagen secretion normally precedes cuticle matrix assembly by several hours, requiring a new way of thinking about cuticle layer formation. Furthermore, in both bli-4 mutants and N-terminal cleavage site mutants, collagens were not secreted efficiently and instead formed intracellular puncta. These data reveal an unexpected role for N-terminal cleavage in cuticle collagen secretion, which could be relevant to the cell biology of human matrix disorders. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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