Functions of Vertebrate Ferlins

Bulankina, Anna V.; Thoms, Sven

doi:10.3390/cells9030534

Cited by 36 publications

(59 citation statements)

References 230 publications

(408 reference statements)

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“…A C2 domain contains 100–130 amino acids and can mediate interaction with membranes by binding Ca 2+ and negatively charged lipids such as phosphatidylserine (PS) or phosphatidylinositol 4,5-bisphosphate (PIP2). In a recent study of Otoferlin C2 domains, the binding of Ca 2+ was indicated for all C2 domains with the exception of C2A [ 49 , 50 ] ( Figure 2(a) ). The C2C and C2F domains of Otoferlin preferentially bind PIP2, and PIP2 may target Otoferlin to the presynapse in a calcium-independent manner [ 51 ].…”

Section: Mechanisms Of Ribbon Synapse Damagementioning

confidence: 95%

Protection of Cochlear Ribbon Synapses and Prevention of Hidden Hearing Loss

et al. 2020

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In the auditory system, ribbon synapses are vesicle-associated structures located between inner hair cells (IHCs) and spiral ganglion neurons that are implicated in the modulation of trafficking and fusion of synaptic vesicles at the presynaptic terminals. Synapse loss may result in hearing loss and difficulties with understanding speech in a noisy environment. This phenomenon happens without permanent hearing loss; that is, the cochlear synaptopathy is “hidden.” Recent studies have reported that synapse loss might be critical in the pathogenesis of hidden hearing loss. A better understanding of the molecular mechanisms of the formation, structure, regeneration, and protection of ribbon synapses will assist in the design of potential therapeutic strategies. In this review, we describe and summarize the following aspects of ribbon synapses: (1) functional and structural features, (2) potential mechanisms of damage, (3) therapeutic research on protecting the synapses, and (4) the role of synaptic regeneration in auditory neuropathy and the current options for synapse rehabilitation.

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Section: Mechanisms Of Ribbon Synapse Damagementioning

confidence: 95%

Protection of Cochlear Ribbon Synapses and Prevention of Hidden Hearing Loss

et al. 2020

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“…Dysferlin and otoferlin have been the most studied. Dysferlin is critical for muscle development and functions in vesicular trafficking and lysosome exocytosis during muscle plasma membrane damage repair [ 38 , 87 ]. Dysferlin does not localize to lysosomes in intact myotubes, but dysferlin-containing vesicles fuse with lysosomes upon sarcolemma damage, possibly in response to a raise in [Ca 2+ ] c [ 88 ].…”

Section: Resultsmentioning

confidence: 99%

“…Either way, dual roles in membrane fusion and vesicle trafficking are also seen in the vertebrate ferlins [ 86 ], such as otoferlin in replenishment of synaptic vesicles [ 40 , 41 ] through myosin VI [ 114 , 115 ]. The role of dysferlin in vesicular trafficking in quite diverse [ 38 ], but is also dependent on actin myosin for plasma membrane repair [ 116 ]. Overall, these observations and similarities with vertebrate ferlins indicate that the role of FER1 changes under different conditions organellar trafficking during intracellular replication, and microneme exocytosis upon activation of egress, during gliding and host cell invasion.…”

Section: Resultsmentioning

confidence: 99%

“…Ferlins are defined by a C-terminal TM domain and 5–7 C2 domains, typically organized in three DOC2 domains ( Figure 2 ). Vertebrate ferlins function in the secretory, endocytic and lysosomal pathways with structural and functional importance in health and disease [ 38 ]. Secretion of synaptic vesicles from the inner ear cells upon mechanical stimulation by sound, only a single Ca 2+ -sensor, otoferlin, is required for exocytosis, at the site of secretion, thereby deviating significantly from the standard model of Ca 2+ -dependent exocytosis established in neurons [ 39 , 40 , 41 ].…”

Section: Introductionmentioning

confidence: 99%

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Ferlins and TgDOC2 in Toxoplasma Microneme, Rhoptry and Dense Granule Secretion

Tagoe

Drozda

Falco

et al. 2021

Life

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The host cell invasion process of apicomplexan parasites like Toxoplasma gondii is facilitated by sequential exocytosis of the microneme, rhoptry and dense granule organelles. Exocytosis is facilitated by a double C2 domain (DOC2) protein family. This class of C2 domains is derived from an ancestral calcium (Ca2+) binding archetype, although this feature is optional in extant C2 domains. DOC2 domains provide combinatorial power to the C2 domain, which is further enhanced in ferlins that harbor 5–7 C2 domains. Ca2+ conditionally engages the C2 domain with lipids, membranes, and/or proteins to facilitating vesicular trafficking and membrane fusion. The widely conserved T. gondii ferlins 1 (FER1) and 2 (FER2) are responsible for microneme and rhoptry exocytosis, respectively, whereas an unconventional TgDOC2 is essential for microneme exocytosis. The general role of ferlins in endolysosmal pathways is consistent with the repurposed apicomplexan endosomal pathways in lineage specific secretory organelles. Ferlins can facilitate membrane fusion without SNAREs, again pertinent to the Apicomplexa. How temporal raises in Ca2+ combined with spatiotemporally available membrane lipids and post-translational modifications mesh to facilitate sequential exocytosis events is discussed. In addition, new data on cross-talk between secretion events together with the identification of a new microneme protein, MIC21, is presented.

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“…Thanks to its multiple C2 domains, myoferlin participates in the tethering of vesicles to membranes and to the calcium sensing. An extensive and excellent review has been recently published on the functions of ferlins in vertebrates [22]. Myoferlin expression is increased in a large panel of cancer cells and tumors, where most of the studies described its role in the recycling of membrane receptors (EGFR, IGFR, .…”

Section: Discussionmentioning

confidence: 99%

Myoferlin Is a Yet Unknown Interactor of the Mitochondrial Dynamics’ Machinery in Pancreas Cancer Cells

Anania

Peiffer

Rademaker

et al. 2020

Cancers

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Pancreas ductal adenocarcinoma is one of the deadliest cancers where surgery remains the main survival factor. Mitochondria were described to be involved in tumor aggressiveness in several cancer types including pancreas cancer. We have previously reported that myoferlin controls mitochondrial structure and function, and demonstrated that myoferlin depletion disturbs the mitochondrial dynamics culminating in a mitochondrial fission. In order to unravel the mechanism underlying this observation, we explored the myoferlin localization in pancreatic cancer cells and showed a colocalization with the mitochondrial dynamic machinery element: mitofusin. This colocalization was confirmed in several pancreas cancer cell lines and in normal cell lines as well. Moreover, in pancreas cancer cell lines, it appeared that myoferlin interacted with mitofusin. These discoveries open-up new research avenues aiming at modulating mitofusin function in pancreas cancer.

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Functions of Vertebrate Ferlins

Cited by 36 publications

References 230 publications

Protection of Cochlear Ribbon Synapses and Prevention of Hidden Hearing Loss

Protection of Cochlear Ribbon Synapses and Prevention of Hidden Hearing Loss

Ferlins and TgDOC2 in Toxoplasma Microneme, Rhoptry and Dense Granule Secretion

Myoferlin Is a Yet Unknown Interactor of the Mitochondrial Dynamics’ Machinery in Pancreas Cancer Cells

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