An internal linker and pH biosensing by phosphatidylinositol 5-phosphate regulate the function of the ESCRT-0 component TOM1

IF 4.4 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Structure Pub Date : 2024-08-28 DOI:10.1016/j.str.2024.08.003

Wen Xiong, Tiffany G. Roach, Nicolas Ball, Marija Corluka, Josephine Beyer, Anne M. Brown, Daniel G.S. Capelluto

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Abstract

Target of Myb1 (TOM1) facilitates the transport of endosomal ubiquitinated proteins destined for lysosomal degradation; however, the mechanisms regulating TOM1 during this process remain unknown. Here, we identified an adjacent DXXLL motif-containing region to the TOM1 VHS domain, which enhances its affinity for ubiquitin and can be modulated by phosphorylation. TOM1 is an endosomal phosphatidylinositol 5-phosphate (PtdIns5P) effector under Shigella flexneri infection. We pinpointed a consensus PtdIns5P-binding motif in the VHS domain. We show that PtdIns5P binding by TOM1 is pH-dependent, similarly observed in its binding partner TOLLIP. Under acidic conditions, TOM1 retained its complex formation with TOLLIP, but was unable to bind ubiquitin. S. flexneri infection inhibits pH-dependent endosomal maturation, leading to reduced protein degradation. We propose a model wherein pumping of H⁺ to the cytosolic side of endosomes contributes to the accumulation of TOM1, and possibly TOLLIP, at these sites, thereby promoting PtdIns5P- and pH-dependent signaling, facilitating bacterial survival.

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内部连接体和 5-磷酸磷脂酰肌醇的 pH 生物传感调节 ESCRT-0 成分 TOM1 的功能

TOM1（Target of Myb1）能促进运往溶酶体降解的内体泛素化蛋白质的转运；然而，在这一过程中，TOM1的调控机制仍然未知。在这里，我们发现了与 TOM1 VHS 结构域相邻的含 DXXLL 标记的区域，该区域可增强其对泛素的亲和力，并可通过磷酸化进行调节。TOM1是一种内体磷脂酰肌醇5-磷酸（PtdIns5P）效应器，可用于感染志贺氏菌。我们在 VHS 结构域中找到了一个 PtdIns5P 结合的共识基团。我们发现 TOM1 与 PtdIns5P 的结合受 pH 值的影响，这与其结合伙伴 TOLLIP 的情况类似。在酸性条件下，TOM1 仍能与 TOLLIP 形成复合物，但无法结合泛素。S. flexneri感染抑制了pH依赖性内体成熟，导致蛋白质降解减少。我们提出了一个模型，即向内体的细胞质一侧泵送 H+有助于 TOM1（可能还有 TOLLIP）在这些部位的聚集，从而促进 PtdIns5P 和 pH 依赖性信号传导，促进细菌存活。

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来源期刊

Structure 生物-生化与分子生物学

CiteScore

8.90

自引率

1.80%

发文量

155

审稿时长

3-8 weeks

期刊介绍： Structure aims to publish papers of exceptional interest in the field of structural biology. The journal strives to be essential reading for structural biologists, as well as biologists and biochemists that are interested in macromolecular structure and function. Structure strongly encourages the submission of manuscripts that present structural and molecular insights into biological function and mechanism. Other reports that address fundamental questions in structural biology, such as structure-based examinations of protein evolution, folding, and/or design, will also be considered. We will consider the application of any method, experimental or computational, at high or low resolution, to conduct structural investigations, as long as the method is appropriate for the biological, functional, and mechanistic question(s) being addressed. Likewise, reports describing single-molecule analysis of biological mechanisms are welcome. In general, the editors encourage submission of experimental structural studies that are enriched by an analysis of structure-activity relationships and will not consider studies that solely report structural information unless the structure or analysis is of exceptional and broad interest. Studies reporting only homology models, de novo models, or molecular dynamics simulations are also discouraged unless the models are informed by or validated by novel experimental data; rationalization of a large body of existing experimental evidence and making testable predictions based on a model or simulation is often not considered sufficient.