Ezrin regulates microvillus morphogenesis by promoting distinct activities of Eps8 proteins

Zwaenepoel, Ingrid; Naba, Alexandra; Cunha, Marcel Menezes Lyra Da; Maestro, Laurence Del; Formstecher, Étienne; Louvard, Daniel; Arpin, Monique

doi:10.1091/mbc.e11-07-0588

Cited by 40 publications

(40 citation statements)

References 43 publications

(71 reference statements)

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“…Notably, Eps8L2 lacks IRSp53 binding, which is essential in Eps8 for relieving inhibition of actin-bundling activity (33). Interestingly, in the gut brush border cells, Eps8 activity lengthens microvilli (35), whereas Eps8L1 shortens them (36). A similar mechanism could be present in hair cell stereocilia, where Eps8 would mainly favor the elongation of the taller stereocilia (15,16).…”

Section: Loss Of Eps8l2 Is Associated With Severe Progressive Hearingmentioning

confidence: 96%

Progressive hearing loss and gradual deterioration of sensory hair bundles in the ears of mice lacking the actin-binding protein Eps8L2

Furness

Johnson

Manor

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Mechanotransduction in the mammalian auditory system depends on mechanosensitive channels in the hair bundles that project from the apical surface of the sensory hair cells. Individual stereocilia within each bundle contain a core of tightly packed actin filaments, whose length is dynamically regulated during development and in the adult. We show that the actin-binding protein epidermal growth factor receptor pathway substrate 8 (Eps8)L2, a member of the Eps8-like protein family, is a newly identified hair bundle protein that is localized at the tips of stereocilia of both cochlear and vestibular hair cells. It has a spatiotemporal expression pattern that complements that of Eps8. In the cochlea, whereas Eps8 is essential for the initial elongation of stereocilia, Eps8L2 is required for their maintenance in adult hair cells. In the absence of both proteins, the ordered staircase structure of the hair bundle in the cochlea decays. In contrast to the early profound hearing loss associated with an absence of Eps8, Eps8L2 nullmutant mice exhibit a late-onset, progressive hearing loss that is directly linked to a gradual deterioration in hair bundle morphology. We conclude that Eps8L2 is required for the long-term maintenance of the staircase structure and mechanosensory function of auditory hair bundles. It complements the developmental role of Eps8 and is a candidate gene for progressive age-related hearing loss.deafness | sensory system | ion channel H earing and balance depend on the transduction of mechanical stimuli into electrical signals. Transduction involves activation of mechanically gated ion channels near the tips of the stereocilia, specialized microvilli that form the hair bundles that project from the surface of sensory hair cells (1). Stereocilia have a cytoskeletal core composed of tightly packed, cross-linked, and uniformly polarized actin filaments (2, 3). Stereociliary length is regulated to ensure the characteristic staircase-like structure of each bundle, whose overall size and shape depends on location along the sensory organ (4). In the mammalian cochlea, hair bundles usually include three rows of stereocilia coupled by several types of extracellular links (2, 5). The embryonic and postnatal development of the bundle involves elongation and thickening of stereocilia, as well as elimination of redundant stereocilia (4, 5).In the adult cochlea, the height of stereocilia within each row is similar, not only within a single hair bundle but also between the bundles of adjacent hair cells, indicating a sophisticated level of control over growth (5, 6). Stereociliary growth and maintenance involves actin-binding proteins such as espin (7,8), plastin (9), twinfilin 2 (10), gelsolin (11), and unconventional myosin motors including myosin XVa (12) and myosin IIIa (13). Currently, we do not have a complete molecular understanding of hair bundle structure or how its growth and maintenance are controlled. Recently, we showed that epidermal growth factor receptor pathway substrate 8 (Eps8) (14) is located ...

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Section: Loss Of Eps8l2 Is Associated With Severe Progressive Hearingmentioning

confidence: 96%

Progressive hearing loss and gradual deterioration of sensory hair bundles in the ears of mice lacking the actin-binding protein Eps8L2

Furness

Johnson

Manor

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Actin polymerization and cell surface remodeling in CLIC5A-transfected COS-7 cells It is well established that ezrin phosphorylation can induce the formation of actin-rich apical protrusions Zwaenepoel et al, 2012). We therefore determined whether ectopic CLIC5A expression in COS-7 cells altered actin polymerization and cell surface architecture.…”

Section: Increased Erm Protein Phosphorylation In Cos-7 Cells Expressmentioning

confidence: 97%

Clustered phosphatidylinositol 4,5 bisphosphate accumulation and ezrin phosphorylation in response to CLIC5A

Al-Momany

Alexander

et al. 2014

Journal of Cell Science

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CLIC5A (encoded by CLIC5) is a component of the ezrin-NHERF2-podocalyxin complex in renal glomerular podocyte foot processes. We explored the mechanism(s) by which CLIC5A regulates ezrin function. In COS-7 cells, CLIC5A augmented ezrin phosphorylation without changing ezrin abundance, increased the association of ezrin with the cytoskeletal fraction and enhanced actin polymerization and the formation of cell surface projections. CLIC5A caused the phosphatidylinositol 4,5-bisphosphate [PI(4,5)P 2 ] reporter RFP-PH-PLC to translocate from the cytosol to discrete plasma membrane clusters at the cell surface, where it colocalized with CLIC5A. Transiently expressed HA-PIP5Ka colocalized with GFP-CLIC5A and was pulled from cell lysates by GST-CLIC5A, and silencing of endogenous PIP5Ka abrogated CLIC5A-dependent ERM phosphorylation. N-and C-terminal deletion mutants of CLIC5A, which failed to associate with the plasma membrane, failed to colocalize with PIP5Ka, did not alter the abundance of PI(4,5)P 2 plasma membrane clusters and failed to enhance ezrin phosphorylation. Relative to wild-type mice, in CLIC5-deficient mice, the phosphorylation of glomerular ezrin was diminished and the cytoskeletal association of both ezrin and NHERF2 was reduced. Therefore, the mechanism of CLIC5A action involves clustered plasma membrane PI(4,5)P 2 accumulation through an interaction of CLIC5A with PI(4,5)P 2 -generating kinases, in turn facilitating ezrin activation and actin-dependent cell surface remodeling.

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“…Ezrin/ radixin/moesin (ERM) family proteins were recently reported to bind to Eps8 directly and regulate its functions (24). Furthermore, Eps8 and ERM proteins were recently reported to colocalize at the plasma membrane of membrane blebs (25).…”

Section: Significancementioning

confidence: 99%

A RhoA and Rnd3 cycle regulates actin reassembly during membrane blebbing

Aoki

Maeda

Nagasako

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The actin cytoskeleton usually lies beneath the plasma membrane. When the membrane-associated actin cytoskeleton is transiently disrupted or the intracellular pressure is increased, the plasma membrane detaches from the cortex and protrudes. Such protruded membrane regions are called blebs. However, the molecular mechanisms underlying membrane blebbing are poorly understood. This study revealed that epidermal growth factor receptor kinase substrate 8 (Eps8) and ezrin are important regulators of rapid actin reassembly for the initiation and retraction of protruded blebs. Livecell imaging of membrane blebbing revealed that local reassembly of actin filaments occurred at Eps8-and activated ezrin-positive foci of membrane blebs. Furthermore, we found that a RhoA-ROCKRnd3 feedback loop determined the local reassembly sites of the actin cortex during membrane blebbing.membrane bleb | Rnd3 | Eps8 | actin cortex | cell migration

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Ezrin regulates microvillus morphogenesis by promoting distinct activities of Eps8 proteins

Abstract: The membrane cytoskeleton linker ezrin differentially regulates the activity of Eps8 and Eps8L1a in microvillar actin-F assembly. Eps8L1a displays F-actin capping activity, therefore controlling microvillus length, whereas, as previously shown, Eps8 displays bundling activity.

Cited by 40 publications

References 43 publications

Progressive hearing loss and gradual deterioration of sensory hair bundles in the ears of mice lacking the actin-binding protein Eps8L2

Progressive hearing loss and gradual deterioration of sensory hair bundles in the ears of mice lacking the actin-binding protein Eps8L2

Clustered phosphatidylinositol 4,5 bisphosphate accumulation and ezrin phosphorylation in response to CLIC5A

A RhoA and Rnd3 cycle regulates actin reassembly during membrane blebbing

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