PTBP1 mediates Sertoli cell actin cytoskeleton organization through regulating alternative splicing of actin regulators
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ABSTRACT:
PROVIDER: PRJNA1113639 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29088368_1.fastq.gz | Fastqsanger.gz | |||
| SRR29088368_2.fastq.gz | Fastqsanger.gz | |||
| SRR29088369_1.fastq.gz | Fastqsanger.gz | |||
| SRR29088369_2.fastq.gz | Fastqsanger.gz | |||
| SRR29088370_1.fastq.gz | Fastqsanger.gz |
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Project description:Spermatogenesis is a biological process within the testis that produces haploid spermatozoa for the continuity of species. Sertoli cells are somatic cells in the seminiferous epithelium that orchestrate spermatogenesis. Cyclic reorganization of Sertoli cell actin cytoskeleton is vital for spermatogenesis but the underlying mechanism remains largely unclear. Here we report that RNA-binding protein PTBP1 controls Sertoli cell actin cytoskeleton reorganization by programming alternative splicing of actin cytoskeleton regulators. This splicing control enables ectoplasmic specializations, the actin-based adhesion junctions, to maintain the blood-testis barrier and support spermatid transport and transformation. Of particular, we show that PTBP1 promotes actin bundle formation by repressing the inclusion of exon 14 of Tnik, a kinase present at the ectoplasmic specialization. Our results thus reveal a novel mechanism wherein Sertoli cell actin cytoskeleton dynamics is controlled post-transcriptionally by utilizing functionally distinct isoforms of actin regulatory proteins and PTBP1 is a key player in generating such isoforms.
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Project description:Sertoli cells are highly polarized testicular cells that provide a nurturing environment for germ cell development and maturation during spermatogenesis. The Class III PI3K, PIK3C3/VPS34 plays key roles in endosomal membrane traffic and macroautophagy in various cell types; however, its role in Sertoli cells remains unclear. Here, we generated a mouse line in which Pik3c3 was specifically deleted in Sertoli cells (cKO) and found that after one round of normal spermatogenesis, the cKO mice quickly became infertile and showed disruption of Sertoli cell polarity, loss of germ cells and impaired spermiogenesis. Subsequent proteomics and phosphoproteomics analyses enriched the F-actin cytoskeleton network involved in the disorganized Sertoli-cell structure in cKO testis, and showed significantly increased expression of the F-actin negative regulator SCIN and reduced phosphorylation of the α-tubulin deacetylase HDAC6. Our results further demonstrated that the accumulation of SCIN in cKO Sertoli cells caused the disassembly of the F-actin cytoskeleton, which was related to the failure of SCIN degradation through the autophagy-lysosome pathway. Additionally, we found that the phosphorylation of HDAC6 at site S59 by PIK3C3 was essential for its degradation through the ubiquitin-proteasome pathway. As a result, the HDAC6 that accumulated in cKO Sertoli cells deacetylated SCIN at site K189 and led to a disorganized F-actin cytoskeleton. Taken together, our findings elucidate the indispensable role of PIK3C3 in maintaining Sertoli cell polarity and reveal a new mechanism in which both its protein kinase activity and its regulation of autophagy are required for the stabilization of the actin cytoskeleton.
2024-08-09 | PXD036240 | Pride
Project description:Sertoli cells are highly polarized testicular cells that provide a nurturing environment for germ cell development and maturation during spermatogenesis. The Class III PI3K, PIK3C3/VPS34 plays key roles in endosomal membrane traffic and macroautophagy in various cell types; however, its role in Sertoli cells remains unclear. Here, we generated a mouse line in which Pik3c3 was specifically deleted in Sertoli cells (cKO) and found that after one round of normal spermatogenesis, the cKO mice quickly became infertile and showed disruption of Sertoli cell polarity, loss of germ cells and impaired spermiogenesis. Subsequent proteomics and phosphoproteomics analyses enriched the F-actin cytoskeleton network involved in the disorganized Sertoli-cell structure in cKO testis, and showed significantly increased expression of the F-actin negative regulator SCIN and reduced phosphorylation of the α-tubulin deacetylase HDAC6. Our results further demonstrated that the accumulation of SCIN in cKO Sertoli cells caused the disassembly of the F-actin cytoskeleton, which was related to the failure of SCIN degradation through the autophagy-lysosome pathway. Additionally, we found that the phosphorylation of HDAC6 at site S59 by PIK3C3 was essential for its degradation through the ubiquitin-proteasome pathway. As a result, the HDAC6 that accumulated in cKO Sertoli cells deacetylated SCIN at site K189 and led to a disorganized F-actin cytoskeleton. Taken together, our findings elucidate the indispensable role of PIK3C3 in maintaining Sertoli cell polarity and reveal a new mechanism in which both its protein kinase activity and its regulation of autophagy are required for the stabilization of the actin cytoskeleton.
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Project description:We describe a new mutant allele of the ACTIN2 gene with enhanced actin dynamics, displaying a broad array of twisting and bending phenotypes that resemble BR-treated plants. Moreover, auxin transcriptional regulation is enhanced on the mutant background, supporting the idea that shaping actin filaments is sufficient to modulate BR-mediated auxin responsiveness. The actin cytoskeleton thus functions as a scaffold for integration of auxin and BR signaling pathways. Three biological replicates were performed for each sample (wild-type and actin2-5) and hybridized to the the Affymetrix ATH1 GeneChips.
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Project description:The actin cytoskeleton is a three-dimensional scaffold of proteins that is a regulatory, energy-consuming material with dynamic properties shaping the structure and function of the cell. The proper function of actin is required for many cellular pathways, including cell division, autophagy, chaperone function, endocytosis, and exocytosis (1–5). The breakdown of these cellular processes manifests during aging and exposure to stress, which is in part due to the breakdown of the actin cytoskeleton (5–9). However, the regulatory mechanisms involved in preservation of cytoskeletal form and function are not well understood. Here, we performed a multi-pronged, cross-organismal screen combining a whole-genome CRISPR-Cas9 screen in human fibroblasts with in vivo C. elegans synthetic lethality screening. We identified the bromodomain protein, BET-1, as a key regulator promoting actin health and longevity. Interestingly, overexpression of bet-1 preserves actin health at late age and promotes lifespan and healthspan in C. elegans. These beneficial effects are through preservation of actin, downstream of the function of BET-1 as a transcriptional regulator. Together, our discovery attributes assigns a key role of BET-1 in cytoskeletal health, highlighting regulatory cellular networks promoting cytoskeletal homeostasis.
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Project description:The actin cytoskeleton is a three-dimensional scaffold of proteins that is a regulatory, energy-consuming material with dynamic properties shaping the structure and function of the cell. The proper function of actin is required for many cellular pathways, including cell division, autophagy, chaperone function, endocytosis, and exocytosis (1–5). The breakdown of these cellular processes manifests during aging and exposure to stress, which is in part due to the breakdown of the actin cytoskeleton (5–9). However, the regulatory mechanisms involved in preservation of cytoskeletal form and function are not well understood. Here, we performed a multi-pronged, cross-organismal screen combining a whole-genome CRISPR-Cas9 screen in human fibroblasts with in vivo C. elegans synthetic lethality screening. We identified the bromodomain protein, BET-1, as a key regulator promoting actin health and longevity. Interestingly, overexpression of bet-1 preserves actin health at late age and promotes lifespan and healthspan in C. elegans. These beneficial effects are through preservation of actin, downstream of the function of BET-1 as a transcriptional regulator. Together, our discovery attributes assigns a key role of BET-1 in cytoskeletal health, highlighting regulatory cellular networks promoting cytoskeletal homeostasis.
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