A melanosomal two-pore sodium channel regulates pigmentation

Abstract Intracellular organelles mediate complex cellular functions that often require ion transport across their membranes. Melanosomes are organelles responsible for the synthesis of the major mammalian pigment melanin. Defects in melanin synthesis result in pigmentation defects, visual deficits, and increased susceptibility to skin and eye cancers. Although genes encoding putative melanosomal ion transporters have been identified as key regulators of melanin synthesis, melanosome ion transport and its contribution to pigmentation remain poorly understood. Here we identify two-pore channel 2 (TPC2) as the first reported melanosomal cation conductance by directly patch-clamping skin and eye melanosomes. TPC2 has been implicated in human pigmentation and melanoma, but the molecular mechanism mediating this function was entirely unknown. We demonstrate that the vesicular signaling lipid phosphatidylinositol bisphosphate PI(3,5)P2 modulates TPC2 activity to control melanosomal membrane potential, pH, and regulate pigmentation.

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Mitochondrial Dynamics, ROS, and Cell Signaling: A Blended Overview

Life ◽

10.3390/life11040332 ◽

2021 ◽

Vol 11 (4) ◽

pp. 332

Author(s):

Valentina Brillo ◽

Leonardo Chieregato ◽

Luigi Leanza ◽

Silvia Muccioli ◽

Roberto Costa

Keyword(s):

Molecular Mechanisms ◽

Mitochondrial Dynamics ◽

Eukaryotic Cells ◽

Therapeutic Approaches ◽

Cellular Functions ◽

Lipid Trafficking ◽

Mitochondrial Ros ◽

Intracellular Organelles ◽

Proliferation Regulation ◽

Dynamic Plasticity

Mitochondria are key intracellular organelles involved not only in the metabolic state of the cell, but also in several cellular functions, such as proliferation, Calcium signaling, and lipid trafficking. Indeed, these organelles are characterized by continuous events of fission and fusion which contribute to the dynamic plasticity of their network, also strongly influenced by mitochondrial contacts with other subcellular organelles. Nevertheless, mitochondria release a major amount of reactive oxygen species (ROS) inside eukaryotic cells, which are reported to mediate a plethora of both physiological and pathological cellular functions, such as growth and proliferation, regulation of autophagy, apoptosis, and metastasis. Therefore, targeting mitochondrial ROS could be a promising strategy to overcome and hinder the development of diseases such as cancer, where malignant cells, possessing a higher amount of ROS with respect to healthy ones, could be specifically targeted by therapeutic treatments. In this review, we collected the ultimate findings on the blended interplay among mitochondrial shaping, mitochondrial ROS, and several signaling pathways, in order to contribute to the dissection of intracellular molecular mechanisms involved in the pathophysiology of eukaryotic cells, possibly improving future therapeutic approaches.

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Hyperosmotic and isosmotic shrinkage differentially affect protein phosphorylation and ion transport

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y11-119 ◽

2012 ◽

Vol 90 (2) ◽

pp. 209-217 ◽

Cited By ~ 3

Author(s):

Svetlana V. Koltsova ◽

Olga A. Akimova ◽

Sergei V. Kotelevtsev ◽

Ryszard Grygorczyk ◽

Sergei N. Orlov

Keyword(s):

Ion Transport ◽

Protein Phosphorylation ◽

Cell Volume ◽

Mdck Cells ◽

Rat Aorta ◽

Cellular Functions ◽

Hypertonic Medium ◽

Mitogen Activated Protein ◽

Volume Decrease ◽

In Cells

In the present work, we compared the outcome of hyperosmotic and isosmotic shrinkage on ion transport and protein phosphorylation in C11-MDCK cells resembling intercalated cells from collecting ducts and in vascular smooth muscle cells (VSMC) from the rat aorta. Hyperosmotic shrinkage was triggered by cell exposure to hypertonic medium, whereas isosmotic shrinkage was evoked by cell transfer from an hypoosmotic to an isosmotic environment. Despite a similar cell volume decrease of 40%–50%, the consequences of hyperosmotic and isosmotic shrinkage on cellular functions were sharply different. In C11-MDCK and VSMC, hyperosmotic shrinkage completely inhibited Na+,K+-ATPase and Na+,Pi cotransport. In contrast, in both types of cells isosmotic shrinkage slightly increased rather than suppressed Na+,K+-ATPase and did not change Na+,Pi cotransport. In C11-MDCK cells, phosphorylation of JNK1/2 and Erk1/2 mitogen-activated protein kinases was augmented in hyperosmotically shrunken cells by ∼7- and 2-fold, respectively, but was not affected in cells subjected to isosmotic shrinkage. These results demonstrate that the data obtained in cells subjected to hyperosmotic shrinkage cannot be considered as sufficient proof implicating cell volume perturbations in the regulation of cellular functions under isosmotic conditions.

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Elucidating the regulatory mechanism of Swi1 prion in global transcription and stress responses

Scientific Reports ◽

10.1038/s41598-020-77993-0 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Zhiqiang Du ◽

Jeniece Regan ◽

Elizabeth Bartom ◽

Wei-Sheng Wu ◽

Li Zhang ◽

...

Keyword(s):

Stress Responses ◽

Regulation Of Transcription ◽

Interacting Proteins ◽

Environmental Stress Response ◽

Key Factors ◽

Cellular Functions ◽

Beneficial Effects ◽

Genome Wide ◽

Genes Encoding ◽

A Subunit

AbstractTranscriptional regulators are prevalent among identified prions in Saccharomyces cerevisiae, however, it is unclear how prions affect genome-wide transcription. We show here that the prion ([SWI+]) and mutant (swi1∆) forms of Swi1, a subunit of the SWI/SNF chromatin-remodeling complex, confer dramatically distinct transcriptomic profiles. In [SWI+] cells, genes encoding for 34 transcription factors (TFs) and 24 Swi1-interacting proteins can undergo transcriptional modifications. Several TFs show enhanced aggregation in [SWI+] cells. Further analyses suggest that such alterations are key factors in specifying the transcriptomic signatures of [SWI+] cells. Interestingly, swi1∆ and [SWI+] impose distinct and oftentimes opposite effects on cellular functions. Translation-associated activities, in particular, are significantly reduced in swi1∆ cells. Although both swi1∆ and [SWI+] cells are similarly sensitive to thermal, osmotic and drought stresses, harmful, neutral or beneficial effects were observed for a panel of tested chemical stressors. Further analyses suggest that the environmental stress response (ESR) is mechanistically different between swi1∆ and [SWI+] cells—stress-inducible ESR (iESR) are repressed by [SWI+] but unchanged by swi1∆ while stress-repressible ESR (rESR) are induced by [SWI+] but repressed by swi1∆. Our work thus demonstrates primarily gain-of-function outcomes through transcriptomic modifications by [SWI+] and highlights a prion-mediated regulation of transcription and phenotypes in yeast.

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Recurrent de novo missense variants in GNB2 can cause syndromic intellectual disability

Journal of Medical Genetics ◽

10.1136/jmedgenet-2020-107462 ◽

2021 ◽

pp. jmedgenet-2020-107462

Author(s):

Natalie B Tan ◽

Alistair T Pagnamenta ◽

Matteo P Ferla ◽

Jonathan Gadian ◽

Brian HY Chung ◽

...

Keyword(s):

Intellectual Disability ◽

G Proteins ◽

De Novo ◽

Neurodevelopmental Disorder ◽

Missense Variant ◽

Cellular Functions ◽

Missense Variants ◽

Neurodevelopmental Disease ◽

Genes Encoding ◽

International Data

PurposeBinding proteins (G-proteins) mediate signalling pathways involved in diverse cellular functions and comprise Gα and Gβγ units. Human diseases have been reported for all five Gβ proteins. A de novo missense variant in GNB2 was recently reported in one individual with developmental delay/intellectual disability (DD/ID) and dysmorphism. We aim to confirm GNB2 as a neurodevelopmental disease gene, and elucidate the GNB2-associated neurodevelopmental phenotype in a patient cohort.MethodsWe discovered a GNB2 variant in the index case via exome sequencing and sought individuals with GNB2 variants via international data-sharing initiatives. In silico modelling of the variants was assessed, along with multiple lines of evidence in keeping with American College of Medical Genetics and Genomics guidelines for interpretation of sequence variants.ResultsWe identified 12 unrelated individuals with five de novo missense variants in GNB2, four of which are recurrent: p.(Ala73Thr), p.(Gly77Arg), p.(Lys89Glu) and p.(Lys89Thr). All individuals have DD/ID with variable dysmorphism and extraneurologic features. The variants are located at the universally conserved shared interface with the Gα subunit, which modelling suggests weaken this interaction.ConclusionMissense variants in GNB2 cause a congenital neurodevelopmental disorder with variable syndromic features, broadening the spectrum of multisystem phenotypes associated with variants in genes encoding G-proteins.

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Pan-Cancer Analysis of the Genomic Alterations and Mutations of the Matrisome

Cancers ◽

10.3390/cancers12082046 ◽

2020 ◽

Vol 12 (8) ◽

pp. 2046 ◽

Cited By ~ 2

Author(s):

Valerio Izzi ◽

Martin N. Davis ◽

Alexandra Naba

Keyword(s):

Cancer Progression ◽

Protein Function ◽

The Cancer Genome Atlas ◽

Copy Number Alterations ◽

Cellular Functions ◽

Genomic Alterations ◽

Genes Encoding ◽

Cancer Genome Atlas ◽

Biomechanical Changes ◽

Pan Cancer

The extracellular matrix (ECM) is a master regulator of all cellular functions and a major component of the tumor microenvironment. We previously defined the “matrisome” as the ensemble of genes encoding ECM proteins and proteins modulating ECM structure or function. While compositional and biomechanical changes in the ECM regulate cancer progression, no study has investigated the genomic alterations of matrisome genes in cancers and their consequences. Here, mining The Cancer Genome Atlas (TCGA) data, we found that copy number alterations and mutations are frequent in matrisome genes, even more so than in the rest of the genome. We also found that these alterations are predicted to significantly impact gene expression and protein function. Moreover, we identified matrisome genes whose mutational burden is an independent predictor of survival. We propose that studying genomic alterations of matrisome genes will further our understanding of the roles of this compartment in cancer progression and will lead to the development of innovative therapeutic strategies targeting the ECM.

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Cellular structure and function

Oxford Handbook of Medical Sciences ◽

10.1093/med/9780198789895.003.0001 ◽

2021 ◽

pp. 1-104

Keyword(s):

Plasma Membrane ◽

Nucleic Acids ◽

Cellular Structure ◽

Structure And Function ◽

The Body ◽

Signalling Pathways ◽

Cellular Functions ◽

Pharmacological Agents ◽

Intracellular Organelles ◽

And Function

‘Cellular structure and function’ covers the roles, structures, and functions of the main four types of macromolecules of the human body, namely proteins, lipids, carbohydrates, and nucleic acids. For these macromolecules, the roles and types of each class are discussed (for proteins this includes their roles as structural proteins and enzymes and their kinetics; for lipids, the roles and types of lipid found in the body are considered; for carbohydrates, their roles including structural and metabolic are discussed; and the structure of nucleic acids is described). Then follows a description of the organization of the cell, including the plasma membrane and its components, and the intracellular organelles. Cell growth, division, and apoptosis are covered, as are the formation of gametes, and finally the principles of how cellular functions can be modulated by pharmacological agents through receptors and signalling pathways are discussed.

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Membrane re-modelling by BAR domain superfamily proteins via molecular and non-molecular factors

Biochemical Society Transactions ◽

10.1042/bst20170322 ◽

2018 ◽

Vol 46 (2) ◽

pp. 379-389 ◽

Cited By ~ 23

Author(s):

Tamako Nishimura ◽

Nobuhiro Morone ◽

Shiro Suetsugu

Keyword(s):

Lipid Membranes ◽

Intracellular Transport ◽

Lipid Membrane ◽

Membrane Curvature ◽

Membrane Dynamics ◽

Cytoskeletal Proteins ◽

Cellular Functions ◽

High Concentration ◽

Bar Domain ◽

Intracellular Organelles

Lipid membranes are structural components of cell surfaces and intracellular organelles. Alterations in lipid membrane shape are accompanied by numerous cellular functions, including endocytosis, intracellular transport, and cell migration. Proteins containing Bin–Amphiphysin–Rvs (BAR) domains (BAR proteins) are unique, because their structures correspond to the membrane curvature, that is, the shape of the lipid membrane. BAR proteins present at high concentration determine the shape of the membrane, because BAR domain oligomers function as scaffolds that mould the membrane. BAR proteins co-operate with various molecular and non-molecular factors. The molecular factors include cytoskeletal proteins such as the regulators of actin filaments and the membrane scission protein dynamin. Lipid composition, including saturated or unsaturated fatty acid tails of phospholipids, also affects the ability of BAR proteins to mould the membrane. Non-molecular factors include the external physical forces applied to the membrane, such as tension and friction. In this mini-review, we will discuss how the BAR proteins orchestrate membrane dynamics together with various molecular and non-molecular factors.

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Genes Encoding Cher-TPR Fusion Proteins Are Predominantly Found in Gene Clusters Encoding Chemosensory Pathways with Alternative Cellular Functions

PLoS ONE ◽

10.1371/journal.pone.0045810 ◽

2012 ◽

Vol 7 (9) ◽

pp. e45810 ◽

Cited By ~ 4

Author(s):

Francisco Muñoz-Martínez ◽

Cristina García-Fontana ◽

Miriam Rico-Jiménez ◽

Carlos Alfonso ◽

Tino Krell

Keyword(s):

Fusion Proteins ◽

Gene Clusters ◽

Cellular Functions ◽

Genes Encoding ◽

Chemosensory Pathways

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A critical role for Apc in hematopoietic stem and progenitor cell survival

Journal of Experimental Medicine ◽

10.1084/jem.20080578 ◽

2008 ◽

Vol 205 (9) ◽

pp. 2163-2175 ◽

Cited By ~ 50

Author(s):

Zhijian Qian ◽

Lina Chen ◽

Anthony A. Fernald ◽

Bart O. Williams ◽

Michelle M. Le Beau

Keyword(s):

Chromosome Segregation ◽

Bone Marrow Failure ◽

Critical Role ◽

Cellular Functions ◽

Erythroid Progenitor ◽

Hematopoietic Stem ◽

Myeloid Progenitor ◽

Cell Cycle Entry ◽

Genes Encoding

The adenomatous polyposis coli (Apc) tumor suppressor is involved in the initiation and progression of colorectal cancer via regulation of the Wnt signaling cascade. In addition, Apc plays an important role in multiple cellular functions, including cell migration and adhesion, spindle assembly, and chromosome segregation. However, its role during adult hematopoiesis is unknown. We show that conditional inactivation of Apc in vivo dramatically increases apoptosis and enhances cell cycle entry of hematopoietic stem cells (HSCs)/ hematopoietic progenitor cells (HPCs), leading to their rapid disappearance and bone marrow failure. The defect in HSCs/HPCs caused by Apc ablation is cell autonomous. In addition, we found that loss of Apc leads to exhaustion of the myeloid progenitor pool (common myeloid progenitor, granulocyte-monocyte progenitor, and megakaryocyte-erythroid progenitor), as well as the lymphoid-primed multipotent progenitor pool. Down-regulation of the genes encoding Cdkn1a, Cdkn1b, and Mcl1 occurs after acute Apc excision in candidate HSC populations. Together, our data demonstrate that Apc is essential for HSC and HPC maintenance and survival.

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Genome-Wide Characterization of Peptidyl-Prolyl Cis-Trans Isomerases in Penicillium and Their Regulation By Salt Stress in a Halotolerant P. Oxalicum

10.21203/rs.3.rs-223100/v1 ◽

2021 ◽

Author(s):

Mangaljeet Singh ◽

Kirandeep Kaur ◽

Avinash Sharma ◽

Rajvir Kaur ◽

Dimple Joshi ◽

...

Keyword(s):

Salt Stress ◽

Gene Families ◽

Peptide Bond ◽

Penicillium Oxalicum ◽

Cellular Functions ◽

Ppiase Activity ◽

Genome Wide ◽

Genes Encoding ◽

Penicillium Spp

Abstract Peptidyl-prolyl cis-trans isomerases (PPIases) are the only class of enzymes capable of cis-trans isomerization of the prolyl peptide bond. The PPIases, comprising of different families viz., cyclophilins, FK506-binding proteins (FKBPs), parvulins and protein phosphatase 2A phosphatase activators (PTPAs), play essential roles in different cellular processes. Though PPIase gene families have been characterized in different organisms, information regarding these proteins lacks in Penicillium species, which are commercially an important fungi group. In this study, we carried out genome-wide analysis of PPIases in different Penicillium spp. and investigated their regulation by salt stress in a halotolerant strain of Penicillium oxalicum. These analyses revealed that the number of genes encoding cyclophilins, FKBPs, parvulins and PTPAs in Penicillium spp. varies between 7-11, 2-5, 1-2, and 1-2, respectively. The halotolerant P. oxalicum depicted significant enhancement in the mycelial PPIase activity in the presence of 15% NaCl, thus, highlighting the role of these enzymes in salt stress adaptation. The PPIase activity in P. oxalicum was associated with the expression of PoxCYP18, PoxCYP23, PoxCYP41, PoxFKBP12-2, and PoxFKBP52 genes. Characterization of PPIases in Penicillium spp. will provide an important database for understanding their cellular functions and might facilitate their applications in industrial processes through biotechnological interventions.

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