Dataset Information

IRTKS (BAIAP2L1) Elongates Epithelial Microvilli Using EPS8-Dependent and Independent Mechanisms.

ABSTRACT: Transporting epithelial cells like those that line the gut build large arrays of actin-supported protrusions called microvilli, which extend from the apical surface into luminal spaces to increase functional surface area. Although critical for maintaining physiological homeostasis, mechanisms controlling the formation of microvilli remain poorly understood. Here, we report that the inverse-bin-amphiphysin-Rvs (I-BAR)-domain-containing protein insulin receptor tyrosine kinase substrate (IRTKS) (also known as BAIAP2L1) promotes the growth of epithelial microvilli. Super-resolution microscopy and live imaging of differentiating epithelial cells revealed that IRTKS localizes to the distal tips of actively growing microvilli via a mechanism that requires its N-terminal I-BAR domain. At microvillar tips, IRTKS promotes elongation through a mechanism involving its C-terminal actin-binding WH2 domain. IRTKS can also drive microvillar elongation using its SH3 domain to recruit the bundling protein EPS8 to microvillar tips. These results provide new insight on mechanisms that control microvillar growth during the differentiation of transporting epithelial cells and help explain why IRTKS is targeted by enteric pathogens that disrupt microvillar structure during infection of the intestinal epithelium.

SUBMITTER: Postema MM

PROVIDER: S-EPMC6156988 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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IRTKS (BAIAP2L1) Elongates Epithelial Microvilli Using EPS8-Dependent and Independent Mechanisms.

Postema Meagan M MM Grega-Larson Nathan E NE Neininger Abigail C AC Tyska Matthew J MJ

Current biology : CB 20180906 18

Transporting epithelial cells like those that line the gut build large arrays of actin-supported protrusions called microvilli, which extend from the apical surface into luminal spaces to increase functional surface area. Although critical for maintaining physiological homeostasis, mechanisms controlling the formation of microvilli remain poorly understood. Here, we report that the inverse-bin-amphiphysin-Rvs (I-BAR)-domain-containing protein insulin receptor tyrosine kinase substrate (IRTKS) (a ...[more]

PMID: 30197089

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Project description:Background & aimsCrohn disease (CD) presents as chronic and often progressive intestinal inflammation, but the contributing pathogenic mechanisms are unclear. We aimed to identify alterations in intestinal cells that could contribute to the chronic and progressive course of CD.MethodsWe took an unbiased system-wide approach by performing sequence analysis of RNA extracted from formalin-fixed paraffin-embedded ileal tissue sections from patients with CD (n = 36) and without CD (controls; n = 32). We selected relatively uninflamed samples, based on histology, before gene expression profiling; validation studies were performed using adjacent serial tissue sections. A separate set of samples (3 control and 4 CD samples) was analyzed by transmission electron microscopy. We developed methods to visualize an overlapping modular network of genes dysregulated in the CD samples. We validated our findings using biopsy samples (110 CD samples for gene expression analysis and 54 for histologic analysis) from the UNITI-2 phase 3 trial of ustekinumab for patients with CD and healthy individuals (26 samples used in gene expression analysis).ResultsWe identified gene clusters that were altered in nearly all CD samples. One cluster encoded genes associated with the enterocyte brush border, leading us to investigate microvilli. In ileal tissues from patients with CD, the microvilli were of decreased length and had ultrastructural defects compared with tissues from controls. Microvilli length correlated with expression of genes that regulate microvilli structure and function. Network analysis linked the microvilli cluster to several other down-regulated clusters associated with altered intracellular trafficking and cellular metabolism. Enrichment of a core microvilli gene set also was lower in the UNITI-2 trial CD samples compared with controls; expression of microvilli genes was correlated with microvilli length and endoscopy score and was associated with response to treatment.ConclusionsIn a transcriptome analysis of formalin-fixed and paraffin-embedded ileal tissues from patients with CD and controls, we associated transcriptional alterations with histologic alterations, such as differences in microvilli length. Decreased microvilli length and decreased expression of the microvilli gene set might contribute to epithelial malfunction and the chronic and progressive disease course in patients with CD.

Dataset Information

IRTKS (BAIAP2L1) Elongates Epithelial Microvilli Using EPS8-Dependent and Independent Mechanisms.

Publications

IRTKS (BAIAP2L1) Elongates Epithelial Microvilli Using EPS8-Dependent and Independent Mechanisms.

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