Instruct: Identify the main category of Biorxiv papers based on the titles and abstracts
Query: XBP1s-Mediated Endoplasmic Reticulum Proteostasis Network Enhancement Can Selectively Improve Folding and Secretion of an Osteogenesis Imperfecta-Causing Collagen-I Variant Osteogenesis imperfecta (OI) is typically caused by autosomal dominant mutations in genes encoding collagen type-I, most commonly resulting in Gly[-&gt;]Ser triple-helical domain substitutions that disrupt collagen folding and/or stability. Here, we test the hypothesis that upregulating the endoplasmic reticulum (ER) proteostasis network via the unfolded protein response (UPR) can improve the folding and secretion of the clinically severe, prototypical OI-causing COL1A1 p.G425S collagen-1(I) variant. We first show that small molecule stressors that globally activate the UPR severely ablate collagen-I secretion from both G425S Col1(I)- and wild-type (WT) Col1(I)-expressing primary fibroblasts. In contrast, stress-independent, specific induction of just the UPRs XBP1s transcriptional response enhances collagen-I secretion from G425S Col1(I) patient primary fibroblasts up to ~300% of basal levels. Notably, the effect is selective - collagen-I secretion from WT Col1(I)-expressing healthy donor primary fibroblasts is unaltered by XBP1s. XBP1s pathway activation appears to post-translationally enhance the folding/assembly and secretion of G425S Col1(I), as only modest impacts on collagen-I transcription or synthesis are observed. Consistent with this notion, we find that the stable, triple-helical collagen-I secreted by XBP1s-activated G425S 1(I) patient fibroblasts includes a higher proportion of the mutant 1(I) polypeptide than the collagen-I secreted under basal ER proteostasis conditions. These results highlight the potential for ER proteostasis network modulation to improve mutant collagen proteostasis in the collagenopathies, motivating further investigation of the effects generality, underlying mechanism, and potential therapeutic benefits.
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The categories of this paper are: animal
21
The categories of this paper are: toxicology
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The categories of this paper are: neuroscience
26
The categories of this paper are: biochemistry
11
The categories of this paper are: cognition
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The categories of this paper are: developmental
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The categories of this paper are: synthetic
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The categories of this paper are: plant
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The categories of this paper are: education
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The categories of this paper are: evolutionary
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The categories of this paper are: and
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The categories of this paper are: immunology
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The categories of this paper are: pathology
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The categories of this paper are: physiology
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The categories of this paper are: pharmacology
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The categories of this paper are: epidemiology