PIKfyve complex regulates early melanosome homeostasis required for physiological amyloid formation

Bissig, Christin; Croisé, Pauline; Heiligenstein, Xavier; Hurbain, Ilse; Lenk, Guy M.; Kaufman, Emily; Sannerud, Ragna; Annaert, Wim; Meisler, Miriam H.; Weisman, Lois S.; Raposo, Graça; Niel, Guillaume van

doi:10.1242/jcs.229500

Cited by 29 publications

(24 citation statements)

References 81 publications

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“…We set to understand if at least some ROS can prevent lysosome coalescence during PIKfyve inhibition by eliminating these F-actin assemblies on lysosomes. Indeed, PtdIns(3,5)P2 depletion increased the number of F-actin puncta associated with lysosomes detectable by fluorescent-phalloidin staining (Fig 12A , B), as previously reported [58,59]. Interestingly, co-administration of rotenone or CDNB with apilimod reduced F-actin puncta associated with lysosomes (Fig 12A, B).…”

Section: Ros Prevents Lysosome Coalescence By Actin Depolymerizationsupporting

confidence: 87%

Reactive oxygen species prevent lysosome coalescence during PIKfyve inhibition

Saffi

Tang

Fountain

et al. 2019

Preprint

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Acknowledgement:ARPE-1 (RPE) cells stably expressing clathrin heavy chain-eGFP were a kind gift from Dr.Costin Antonescu. We would also like to thank Mr. Janusan Baskararajah for technical assistance. AbstractLysosomes are terminal, degradative organelles of the endosomal pathway that undergo repeated fusion-fission cycles with themselves and other organelles like endosomes, phagosomes, and autophagosomes. Lysosome number, size and degradative flux depends on the equilibrium between fusion and fission rates. Thus, conditions that favour fusion over fission will reduce lysosome numbers while enlarging remaining lysosomes. Conversely, conditions that favour fission over fusion will cause lysosome fragmentation and increase their numbers. PIKfyve is a phosphoinositide kinase that generates phosphatidylinositol-3,5-bisphosphate to modulate several lysosomal functions. PIKfyve inhibition causes a dramatic increase in lysosome size and reduction in lysosome number, consistent with lysosome coalescence. This is thought to proceed through reduced lysosome reformation and/or fission after fusion with endosomes or other lysosomes. Previously, we observed that photo-damage during live-cell imaging prevented lysosome coalescence during acute PIKfyve inhibition. Thus, we postulated that lysosome fusion and/or fission dynamics are affected by reactive oxygen species (ROS). Here, we show that ROS generated by four independent mechanisms all arrested lysosome coalescence during PIKfyve inhibition and accelerated lysosome fragmentation during PIKfyve re-activation.However, depending on the ROS species and/or mode of production, lysosome dynamics were affected distinctly. H2O2 impaired lysosome motility and reduced lysosome fusion with phagosomes, suggesting that H2O2 prevents lysosome coalescence in PIKfyve-impaired cells by reducing lysosome fusogenecity. In comparison, inhibitors of oxidative phosphorylation, glutathione, and thioredoxin that produce superoxide, did not impair lysosome motility but instead promoted clearance of actin puncta on lysosomes formed during PIKfyve inhibition.Additionally, actin depolymerizing agents prevented lysosome coalescence during PIKfyve inhibition. Thus, we discovered that ROS can generally prevent lysosome coalescence during PIKfyve inhibition using distinct mechanisms.Bissig, C., Croisé, P., Heiligenstein, X., Hurbain, I., Lenk, G. M., Kaufman, E., Sannerud, R., Annaert, W., Meisler, M. H., Weisman, L. S., et al. (2019). PIKfyve complex regulates early melanosome homeostasis required for physiological amyloid formation. . Dense core lysosomes can fuse with late endosomes and are re-formed from the resultant hybrid organelles. . (2001). Rab-interacting lysosomal protein (RILP): the Rab7 effector required for transport to lysosomes. EMBO J. 20, 683-93.Cao, Q., Zhong, X. Z., Zou, Y., Murrell-Lagnado, R., Zhu, M. X. and Dong, X.-P. (2015). Calcium release through P2X4 activates calmodulin to promote endolysosomal membrane fusion.

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Section: Ros Prevents Lysosome Coalescence By Actin Depolymerizationsupporting

confidence: 87%

Reactive oxygen species prevent lysosome coalescence during PIKfyve inhibition

Saffi

Tang

Fountain

et al. 2019

Preprint

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“…Melanosome biogenesis also involves proteins such as (BLOC)-1-3, Rab38, Rab32, Cargo, and PYKfyve and adaptor protein complexes that function in melanin trafficking (AP1-3) [119]. The small GTPase Rab27a with melanophilin and myosin Va anchor melanosomes to actin-based motors to deliver melanosomes to the plasma membrane [120] and, subsequently, to keratinocytes.…”

Section: Box 3 Genetic Basis Of Melanogenesismentioning

confidence: 99%

Decoding the Evolution of Melanin in Vertebrates

McNamara

Rossi

Slater

et al. 2021

Trends in Ecology & Evolution

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Melanins are widespread pigments in vertebrates, with important roles in visual signaling, UV protection, and homeostasis. Fossil evidence of melanin and melanin-bearing organellesmelanosomesin ancient vertebrates may illuminate the evolution of melanin and its functions, but macroevolutionary trends are poorly resolved. Here, we integrate fossil data with current understanding of melanin function, biochemistry, and genetics. Mapping key genes onto phenotypic attributes of fossil vertebrates identifies potential genomic controls on melanin evolution. Taxonomic trends in the anatomical location, geometry, and chemistry of vertebrate melanosomes are linked to the evolution of endothermy. These shifts in melanin biology suggest fundamental links between melanization and vertebrate ecology. Tissue-specific and taxonomic trends in melanin chemistry support evidence for evolutionary tradeoffs between function and cytotoxicity. Melanin in Vertebrates Melanins (see Glossary) are dark to rufous pigments that are widespread in vertebrates and underpin critical functions in physiology and behavior [1]. Fossil evidence of melanin extending to over 300 million years ago has triggered a paradigm shift in paleobiology, prompting remarkable reconstructions of the coloration and behavior of extinct vertebrates [2-6]. New discoveries of internal melanins in vertebrate fossils have broadened our understanding of the functional diversity of ancient melanins [7-9] and invite a re-evaluation of the macroevolutionary history of melanin and its functions. Here, we synthesize trends in the fossil record of melanin and explore fossil evidence for the evolution of melanin function and the genetic basis of melanization. This highlights the value of the fossil record as a resource for tracking melanin evolution through deep time. Functions of Melanin in Ancient Vertebrates In extant vertebrates, melanin occurs as micron-sized organelles, melanosomes, in the integument, eyes and internal tissues and functions in photoprotection, visual signaling, thermoregulation, immunity, antioxidation, mechanical strengthening, and abrasion resistance [6,10,11] (Figure 1, Box 1). It is unclear which functions evolved first and which selection pressures dominate [11,12]. Fossils preserving evidence of melanin offer a unique temporal perspective. Melanin has been reported from fossil vertebrates from >25 localities from the Carboniferous to the Pliocene (Table S1 in the supplemental information online). The fossils include cyclostomes, fish, frogs, lizards, and other squamates, ichthyosaurs, plesiosaurs, turtles, pterosaurs, feathered and nonfeathered dinosaurs, birds, and mammals. This phylogenetically and temporally broad dataset yields evidence for ancient functions of melanin (Figure 2). Highlights In extant vertebrates melanin fulfils diverse roles including visual communication, photoprotection, antioxidation, and mechanical strengthening of tissues, but the evolution of these functions is debated. The discovery that melanosomes in fossil and modern ve...

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“…Fluorescent protein conjugates to various melanosomal proteins, expressed in melanocytes by transfection or recombinant virus transduction, have been used to visualize melanosome motility and membrane dynamics to and from melanosomes. The coexpression of fluorescent markers of other compartments, the concomitant visualization of pigment granules by bright field microscopy, or the identification of melanosomes by their characteristic "donut" structure (in which fluorescence in the melanosome interior is quenched by melanin) can reveal dynamic and transient interactions between melanosomes and endosomal transport intermediates (Delevoye et al, 2009;, lysosomes (Bissig et al, 2019), or Golgi-derived vesicles . Such interactions are best captured by spinning disk confocal microscopy.…”

Section: Live Cell Imagingmentioning

confidence: 99%

Research Techniques Made Simple: Cell Biology Methods for the Analysis of Pigmentation

Benito-Martínez

Zhu

Jani

et al. 2020

Journal of Investigative Dermatology

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Pigmentation of the skin and hair represents the result of melanin biosynthesis within melanosomes of epidermal melanocytes, followed by the transfer of mature melanin granules to adjacent keratinocytes within the basal layer of the epidermis. Natural variation in these processes produces the diversity of skin and hair color among human populations, and defects in these processes lead to diseases such as oculocutaneous albinism. While genetic regulators of pigmentation have been well studied in human and animal models, we are still learning much about the cell biological features that regulate melanogenesis, melanosome maturation, and melanosome motility in melanocytes, and have barely scratched the surface in our understanding of melanin transfer from melanocytes to keratinocytes. Herein, we describe cultured cell model systems and common assays that have been used by investigators to dissect these features and that will hopefully lead to additional advances in the future.

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PIKfyve complex regulates early melanosome homeostasis required for physiological amyloid formation

Cited by 29 publications

References 81 publications

Reactive oxygen species prevent lysosome coalescence during PIKfyve inhibition

Reactive oxygen species prevent lysosome coalescence during PIKfyve inhibition

Decoding the Evolution of Melanin in Vertebrates

Research Techniques Made Simple: Cell Biology Methods for the Analysis of Pigmentation

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