Phase separation-mediated condensation of Whirlin-Myo15-Eps8 stereocilia tip complex

Lin, Lin; Shi, Yingdong; Wang, Chao; Lü, Qing; Zhu, Jinwei; Zhang, Rongguang

doi:10.1016/j.celrep.2021.108770

Cited by 20 publications

(41 citation statements)

References 67 publications

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“…6, A and B). The 3xTCD condensates significantly produced more bundled actin filaments, as described in our previous work (14). Consistent with their phase separation abilities (Fig.…”

Section: Xtcd Condensates Induce Robust Actin Bundlingsupporting

confidence: 91%

Promotion of row 1–specific tip complex condensates by Gpsm2-Gαi provides insights into row identity of the tallest stereocilia

et al. 2022

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The mechanosensory stereocilia in hair cells are organized into rows of graded height, a property crucial for auditory perception. Gpsm2-Gαi-Whirlin-Myo15-Eps8 complex at tips of the tallest stereocilia is proposed to define hair bundle row identity, although the underlying mechanism remains elusive. Here, we find that Gpsm2 could undergo phase separation. Moreover, row 1–specific Gpsm2-Gαi complex significantly promotes the formation of the five-component tip complex density (5xTCD) condensates. The 5xTCD condensates display much stronger actin-bundling ability than those without Gpsm2-Gαi, which may provide critical insights into how Gpsm2-Gαi specifies the tallest stereocilia. A deafness-associated mutation of Gpsm2 leads to impaired formation of the 5xTCD condensates and consequently reduced actin bundling, providing possible clues for etiology of hearing loss in patients with Chudley-McCullough syndrome.

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“…6, A and B). The 3xTCD condensates significantly produced more bundled actin filaments, as described in our previous work (14). Consistent with their phase separation abilities (Fig.…”

Section: Xtcd Condensates Induce Robust Actin Bundlingsupporting

confidence: 91%

Promotion of row 1–specific tip complex condensates by Gpsm2-Gαi provides insights into row identity of the tallest stereocilia

et al. 2022

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“…BAIAP2L2 enriches at the tips of those stereocilia, interacts with the actin regulator EPS8, and depends on MYO15A for localization (Carlton et al, 2021;Yan et al, 2021). These results suggested that BAIAP2L2 may be transported by the transduction-regulated MYO15A-EPS8 complex (Ebrahim et al, 2016;Lin et al, 2021;Manor et al, 2011), which carries other hair-bundle proteins (Krey et al, 2020;Tadenev et al, 2019). MYO15A and EPS8 are both essential for normal bundle development; mutants in either gene produce bundles with short, narrow stereocilia (Belyantseva et al, 2003;Zampini et al, 2011).…”

Section: Introductionmentioning

confidence: 98%

Ca²⁺ entry through mechanotransduction channels localizes BAIAP2L2 to stereocilia tips

Halford

Bateschell

Barr-Gillespie

2022

MBoC

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BAIAP2L2, a membrane-binding protein required for maintenance of mechanotransduction in hair cells, is selectively retained at tips of transducing stereocilia. BAIAP2L2 trafficked to stereocilia tips in the absence of EPS8, but EPS8 increased the efficiency of localization. A tripartite complex of BAIAP2L2, EPS8, and MYO15A formed efficiently in vitro, and these three proteins robustly targeted to filopodia tips when co-expressed in cultured cells. Mice lacking functional transduction channels no longer concentrated BAIAP2L2 at row 2 stereocilia tips, a result that was phenocopied by blocking channels with tubocurarine in cochlear explants. Transduction channels permit Ca2+ entry into stereocilia, and we found that membrane localization of BAIAP2L2 was enhanced in the presence of Ca2+. Finally, reduction of intracellular Ca2+ in hair cells using BAPTA-AM led to a loss of BAIAP2L2 at stereocilia tips. Taken together, our results show that a MYO15A-EPS8 complex transports BAIAP2L2 to stereocilia tips, and Ca2+ entry through open channels at row 2 tips retains BAIAP2L2 there.

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“…Whirlin ( WHRN ) is a protein-coding gene. Diseases associated with WHRN include deafness, autosomal recessive hearing loss (DFNB31), and USH2D [ 44 , 45 , 85 , 86 ]. It is necessary for elongation and maintenance of inner and outer hair cell stereocilia and is involved in the maintenance of the hair bundle ankle region (ankle links), which connects the stereocilia of the hair cells.…”

Section: Genetics Of Ushmentioning

confidence: 99%

“…In the retina, WHRN is important for the maintenance of a periciliary membrane complex that seems to play a role in regulating intracellular protein transport in photoreceptors [ 87 , 88 , 89 ]. Lin et al recently reported that whirlin interacts with the EPS8 protein in the tip complex [ 85 ]. This interaction is mediated by the MYO15 protein, which is responsible for DFNB3 when mutated.…”

Section: Genetics Of Ushmentioning

confidence: 99%

“…This interaction is mediated by the MYO15 protein, which is responsible for DFNB3 when mutated. EPS8 encodes an epidermal growth factor protein that is also reported to be responsible for DFNB102 and syndromic hearing loss (branchio-oto-renal syndrome) [ 44 , 45 , 85 , 86 ]. Thus, the roles of genes encoding different USH protein networks are still unclear.…”

Section: Genetics Of Ushmentioning

confidence: 99%

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Usher Syndrome

Castiglione

Möller

2022

Audiology Research

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Usher syndrome (USH) is the most common genetic condition responsible for combined loss of hearing and vision. Balance disorders and bilateral vestibular areflexia are also observed in some cases. The syndrome was first described by Albrecht von Graefe in 1858, but later named by Charles Usher, who presented a large number of cases with hearing loss and retinopathy in 1914. USH has been grouped into three main clinical types: 1, 2, and 3, which are caused by mutations in different genes and are further divided into different subtypes. To date, nine causative genes have been identified and confirmed as responsible for the syndrome when mutated: MYO7A, USH1C, CDH23, PCDH15, and USH1G (SANS) for Usher type 1; USH2A, ADGRV1, and WHRN for Usher type 2; CLRN1 for Usher type 3. USH is inherited in an autosomal recessive pattern. Digenic, bi-allelic, and polygenic forms have also been reported, in addition to dominant or nonsyndromic forms of genetic mutations. This narrative review reports the causative forms, diagnosis, prognosis, epidemiology, rehabilitation, research, and new treatments of USH.

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Phase separation-mediated condensation of Whirlin-Myo15-Eps8 stereocilia tip complex

Cited by 20 publications

References 67 publications

Promotion of row 1–specific tip complex condensates by Gpsm2-Gαi provides insights into row identity of the tallest stereocilia

Promotion of row 1–specific tip complex condensates by Gpsm2-Gαi provides insights into row identity of the tallest stereocilia

Ca²⁺ entry through mechanotransduction channels localizes BAIAP2L2 to stereocilia tips

Usher Syndrome

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Phase separation-mediated condensation of Whirlin-Myo15-Eps8 stereocilia tip complex

Cited by 20 publications

References 67 publications

Promotion of row 1–specific tip complex condensates by Gpsm2-Gαi provides insights into row identity of the tallest stereocilia

Promotion of row 1–specific tip complex condensates by Gpsm2-Gαi provides insights into row identity of the tallest stereocilia

Ca2+ entry through mechanotransduction channels localizes BAIAP2L2 to stereocilia tips

Usher Syndrome

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Ca²⁺ entry through mechanotransduction channels localizes BAIAP2L2 to stereocilia tips