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11 pages, 3217 KiB

Open AccessArticle

Ezrin Regulates Ca²⁺ Ionophore-Induced Plasma Membrane Translocation of Aquaporin-5

by Shin-ichi Muroi and Yoichiro Isohama

Int. J. Mol. Sci. 2021, 22(24), 13505; https://doi.org/10.3390/ijms222413505 - 16 Dec 2021

Cited by 5 | Viewed by 2340

Abstract

Aquaporin-5 (AQP5) is selectively expressed in the apical membrane of exocrine glands, such as salivary, sweat, and submucosal airway glands, and plays important roles in maintaining their secretory functions. Because AQP5 is not regulated by gating, localization on the plasma membrane is important [...] Read more.

Aquaporin-5 (AQP5) is selectively expressed in the apical membrane of exocrine glands, such as salivary, sweat, and submucosal airway glands, and plays important roles in maintaining their secretory functions. Because AQP5 is not regulated by gating, localization on the plasma membrane is important for its water-permeable function. Ezrin is an ezrin–radixin–moesin family protein that serves as a crosslinker between the plasma membrane and actin cytoskeleton network. It plays important roles in translocation of various membrane proteins to mediate vesicle trafficking to the plasma membrane. In this study, we examined the effects of ezrin inhibition on membrane trafficking of AQP5. Ezrin inhibition selectively suppressed an ionomycin-induced increase in AQP5 translocation to the plasma membrane of mouse lung epithelial cells (MLE-12) without affecting the steady-state level of plasma membrane AQP5. Taken together, our data suggest that AQP5 translocates to the plasma membrane through at least two pathways and that ezrin is selectively involved in a stimulation-dependent pathway. Full article

(This article belongs to the Special Issue Molecular Regulatory Mechanisms of Membrane Trafficking)

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12 pages, 1976 KiB

Open AccessArticle

Knockdown of PEX16 Induces Autophagic Degradation of Peroxisomes

by Xiaofan Wei, Yunash Maharjan, Debra Dorotea, Raghbendra-Kumar Dutta, Donghyun Kim, Hyunsoo Kim, Yizhu Mu, Channy Park and Raekil Park

Int. J. Mol. Sci. 2021, 22(15), 7989; https://doi.org/10.3390/ijms22157989 - 26 Jul 2021

Cited by 3 | Viewed by 2734

Abstract

Peroxisome abundance is regulated by homeostasis between the peroxisomal biogenesis and degradation processes. Peroxin 16 (PEX16) is a peroxisomal protein involved in trafficking membrane proteins for de novo peroxisome biogenesis. The present study demonstrates that PEX16 also modulates peroxisome abundance through pexophagic degradation. [...] Read more.

Peroxisome abundance is regulated by homeostasis between the peroxisomal biogenesis and degradation processes. Peroxin 16 (PEX16) is a peroxisomal protein involved in trafficking membrane proteins for de novo peroxisome biogenesis. The present study demonstrates that PEX16 also modulates peroxisome abundance through pexophagic degradation. PEX16 knockdown in human retinal pigment epithelial-1 cells decreased peroxisome abundance and function, represented by reductions in the expression of peroxisome membrane protein ABCD3 and the levels of cholesterol and plasmalogens, respectively. The activation of pexophagy under PEX16 knockdown was shown by (i) abrogated peroxisome loss under PEX16 knockdown in autophagy-deficient ATG5 knockout cell lines, and (ii) increased autophagy flux and co-localization of p62—an autophagy adaptor protein—with ABCD3 in the presence of the autophagy inhibitor chloroquine. However, the levels of cholesterol and plasmalogens did not recover despite the restoration of peroxisome abundance following chloroquine treatment. Thus, PEX16 is indispensable for maintaining peroxisome homeostasis by regulating not only the commonly known biogenesis pathway but also the autophagic degradation of peroxisomes. Full article

(This article belongs to the Special Issue Molecular Regulatory Mechanisms of Membrane Trafficking)

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15 pages, 3144 KiB

Open AccessArticle

Extracellular Vesicles (Secretomes) from Human Trophoblasts Promote the Regeneration of Skin Fibroblasts

by Yoon Young Go, Chan Mi Lee, Won Min Ju, Sung-Won Chae and Jae-Jun Song

Int. J. Mol. Sci. 2021, 22(13), 6959; https://doi.org/10.3390/ijms22136959 - 28 Jun 2021

Cited by 14 | Viewed by 2927

Abstract

To date, placental trophoblasts have been of interest in the fields of obstetrics and gynecology, mainly due to their involvement in the formation of a connection between the mother and fetus that aids in placental development and fetal survival. However, the regenerative capacities [...] Read more.

To date, placental trophoblasts have been of interest in the fields of obstetrics and gynecology, mainly due to their involvement in the formation of a connection between the mother and fetus that aids in placental development and fetal survival. However, the regenerative capacities of trophoblasts for application in regenerative medicine and tissue engineering are poorly understood. Here, we aim to determine the skin regeneration and anti-aging capacities of trophoblast-derived conditioned medium (TB-CM) and exosomes (TB-Exos) using human normal dermal fibroblasts (HNDFs). TB-CM and TB-Exos treatments significantly elevated the migration and proliferation potencies of HNDF cells in a dose- and time-dependent manner. When RNA sequencing (RNA-seq) was used to investigate the mechanism underlying TB-CM-induced cell migration on scratch-wounded HNDFs, the increased expression of genes associated with C-X-C motif ligand (CXCL) chemokines, toll-like receptors, and nuclear factor-kappa B (NF-κB) signaling was observed. Furthermore, treatment of intrinsically/extrinsically senescent HNDFs with TB-CM resulted in an enhanced rejuvenation of HNDFs via both protection and restoration processes. Gene expression of extracellular matrix components in the skin dermis significantly increased in TB-CM- and TB-Exos-treated HNDFs. These components are involved in the TB-CM and Exo-mediated regeneration and anti-aging of HNDFs. Thus, this study demonstrated the regenerative and anti-aging efficacies of trophoblast-derived secretomes, suggesting their potential for use in interventions for skin protection and treatment. Full article

(This article belongs to the Special Issue Molecular Regulatory Mechanisms of Membrane Trafficking)

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16 pages, 2256 KiB

Open AccessArticle

Combination Treatment of OSI-906 with Aurora B Inhibitor Reduces Cell Viability via Cyclin B1 Degradation-Induced Mitotic Slippage

by Yuki Ikeda, Ryuji Yasutake, Ryuzaburo Yuki, Youhei Saito and Yuji Nakayama

Int. J. Mol. Sci. 2021, 22(11), 5706; https://doi.org/10.3390/ijms22115706 - 27 May 2021

Cited by 4 | Viewed by 2896

Abstract

Insulin-like growth factor 1 receptor (IGF1R), a receptor-type tyrosine kinase, transduces signals related to cell proliferation, survival, and differentiation. We recently reported that OSI-906, an IGF1R inhibitor, in combination with the Aurora B inhibitor ZM447439 suppresses cell proliferation. However, the mechanism underlying this [...] Read more.

Insulin-like growth factor 1 receptor (IGF1R), a receptor-type tyrosine kinase, transduces signals related to cell proliferation, survival, and differentiation. We recently reported that OSI-906, an IGF1R inhibitor, in combination with the Aurora B inhibitor ZM447439 suppresses cell proliferation. However, the mechanism underlying this suppressive effect is yet to be elucidated. In this study, we examined the effects of combination treatment with OSI-906 and ZM447439 on cell division, so as to understand how cell proliferation was suppressed. Morphological analysis showed that the combination treatment generated enlarged cells with aberrant nuclei, whereas neither OSI-906 nor ZM447439 treatment alone caused this morphological change. Flow cytometry analysis indicated that over-replicated cells were generated by the combination treatment, but not by the lone treatment with either inhibitors. Time-lapse imaging showed mitotic slippage following a severe delay in chromosome alignment and cytokinesis failure with furrow regression. Furthermore, in S-trityl-l-cysteine–treated cells, cyclin B1 was precociously degraded. These results suggest that the combination treatment caused severe defect in the chromosome alignment and spindle assembly checkpoint, which resulted in the generation of over-replicated cells. The generation of over-replicated cells with massive aneuploidy may be the cause of reduction of cell viability and cell death. This study provides new possibilities of cancer chemotherapy. Full article

(This article belongs to the Special Issue Molecular Regulatory Mechanisms of Membrane Trafficking)

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16 pages, 11410 KiB

Open AccessArticle

Inhibition of HSF1 and SAFB Granule Formation Enhances Apoptosis Induced by Heat Stress

by Kazunori Watanabe and Takashi Ohtsuki

Int. J. Mol. Sci. 2021, 22(9), 4982; https://doi.org/10.3390/ijms22094982 - 7 May 2021

Cited by 9 | Viewed by 3752

Abstract

Stress resistance mechanisms include upregulation of heat shock proteins (HSPs) and formation of granules. Stress-induced granules are classified into stress granules and nuclear stress bodies (nSBs). The present study examined the involvement of nSB formation in thermal resistance. We used chemical compounds that [...] Read more.

Stress resistance mechanisms include upregulation of heat shock proteins (HSPs) and formation of granules. Stress-induced granules are classified into stress granules and nuclear stress bodies (nSBs). The present study examined the involvement of nSB formation in thermal resistance. We used chemical compounds that inhibit heat shock transcription factor 1 (HSF1) and scaffold attachment factor B (SAFB) granule formation and determined their effect on granule formation and HSP expression in HeLa cells. We found that formation of HSF1 and SAFB granules was inhibited by 2,5-hexanediol. We also found that suppression of HSF1 and SAFB granule formation enhanced heat stress-induced apoptosis. In addition, the upregulation of HSP27 and HSP70 during heat stress recovery was suppressed by 2,5-hexanediol. Our results suggested that the formation of HSF1 and SAFB granules was likely to be involved in the upregulation of HSP27 and HSP70 during heat stress recovery. Thus, the formation of HSF1 and SAFB granules was involved in thermal resistance. Full article

(This article belongs to the Special Issue Molecular Regulatory Mechanisms of Membrane Trafficking)

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Review

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12 pages, 1219 KiB

Open AccessReview

Large Rab GTPases: Novel Membrane Trafficking Regulators with a Calcium Sensor and Functional Domains

by Takayuki Tsukuba, Yu Yamaguchi and Tomoko Kadowaki

Int. J. Mol. Sci. 2021, 22(14), 7691; https://doi.org/10.3390/ijms22147691 - 19 Jul 2021

Cited by 9 | Viewed by 3160

Abstract

Rab GTPases are major coordinators of intracellular membrane trafficking, including vesicle transport, membrane fission, tethering, docking, and fusion events. Rab GTPases are roughly divided into two groups: conventional “small” Rab GTPases and atypical “large” Rab GTPases that have been recently reported. Some members [...] Read more.

Rab GTPases are major coordinators of intracellular membrane trafficking, including vesicle transport, membrane fission, tethering, docking, and fusion events. Rab GTPases are roughly divided into two groups: conventional “small” Rab GTPases and atypical “large” Rab GTPases that have been recently reported. Some members of large Rab GTPases in mammals include Rab44, Rab45/RASEF, and Rab46. The genes of these large Rab GTPases commonly encode an amino-terminal EF-hand domain, coiled-coil domain, and the carboxyl-terminal Rab GTPase domain. A common feature of large Rab GTPases is that they express several isoforms in cells. For instance, Rab44’s two isoforms have similar functions, but exhibit differential localization. The long form of Rab45 (Rab45-L) is abundantly distributed in epithelial cells. The short form of Rab45 (Rab45-S) is predominantly present in the testes. Both Rab46 (CRACR2A-L) and the short isoform lacking the Rab domain (CRACR2A-S) are expressed in T cells, whereas Rab46 is only distributed in endothelial cells. Although evidence regarding the function of large Rab GTPases has been accumulating recently, there are only a limited number of studies. Here, we report the recent findings on the large Rab GTPase family concerning their function in membrane trafficking, cell differentiation, related diseases, and knockout mouse phenotypes. Full article

(This article belongs to the Special Issue Molecular Regulatory Mechanisms of Membrane Trafficking)

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13 pages, 1407 KiB

Open AccessReview

Revising Endosomal Trafficking under Insulin Receptor Activation

by Maria J. Iraburu, Tommy Garner and Cristina Montiel-Duarte

Int. J. Mol. Sci. 2021, 22(13), 6978; https://doi.org/10.3390/ijms22136978 - 29 Jun 2021

Cited by 15 | Viewed by 2957

Abstract

The endocytosis of ligand-bound receptors and their eventual recycling to the plasma membrane (PM) are processes that have an influence on signalling activity and therefore on many cell functions, including migration and proliferation. Like other tyrosine kinase receptors (TKR), the insulin receptor (INSR) [...] Read more.

The endocytosis of ligand-bound receptors and their eventual recycling to the plasma membrane (PM) are processes that have an influence on signalling activity and therefore on many cell functions, including migration and proliferation. Like other tyrosine kinase receptors (TKR), the insulin receptor (INSR) has been shown to be endocytosed by clathrin-dependent and -independent mechanisms. Once at the early endosome (EE), the sorting of the receptor, either to the late endosome (LE) for degradation or back to the PM through slow or fast recycling pathways, will determine the intensity and duration of insulin effects. Both the endocytic and the endosomic pathways are regulated by many proteins, the Arf and Rab families of small GTPases being some of the most relevant. Here, we argue for a specific role for the slow recycling route, whilst we review the main molecular mechanisms involved in INSR endocytosis, sorting and recycling, as well as their possible role in cell functions. Full article

(This article belongs to the Special Issue Molecular Regulatory Mechanisms of Membrane Trafficking)

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18 pages, 4332 KiB

Open AccessReview

NFAT5-Mediated Signalling Pathways in Viral Infection and Cardiovascular Dysfunction

by Guangze Zhao, Sana Aghakeshmiri, Yankuan T. Chen, Huifang M. Zhang, Fione Yip and Decheng Yang

Int. J. Mol. Sci. 2021, 22(9), 4872; https://doi.org/10.3390/ijms22094872 - 4 May 2021

Cited by 7 | Viewed by 4518

Abstract

The nuclear factor of activated T cells 5 (NFAT5) is well known for its sensitivity to cellular osmolarity changes, such as in the kidney medulla. Accumulated evidence indicates that NFAT5 is also a sensitive factor to stress signals caused by non-hypertonic stimuli such [...] Read more.

The nuclear factor of activated T cells 5 (NFAT5) is well known for its sensitivity to cellular osmolarity changes, such as in the kidney medulla. Accumulated evidence indicates that NFAT5 is also a sensitive factor to stress signals caused by non-hypertonic stimuli such as heat shock, biomechanical stretch stress, ischaemia, infection, etc. These osmolality-related and -unrelated stimuli can induce NFAT5 upregulation, activation and nuclear accumulation, leading to its protective role against various detrimental effects. However, dysregulation of NFAT5 expression may cause pathological conditions in different tissues, leading to a variety of diseases. These protective or pathogenic effects of NFAT5 are dictated by the regulation of its target gene expression and activation of its signalling pathways. Recent studies have found a number of kinases that participate in the phosphorylation/activation of NFAT5 and related signal proteins. Thus, this review will focus on the NFAT5-mediated signal transduction pathways. As for the stimuli that upregulate NFAT5, in addition to the stresses caused by hyperosmotic and non-hyperosmotic environments, other factors such as miRNA, long non-coding RNA, epigenetic modification and viral infection also play an important role in regulating NFAT5 expression; thus, the discussion in this regard is another focus of this review. As the heart, unlike the kidneys, is not normally exposed to hypertonic environments, studies on NFAT5-mediated cardiovascular diseases are just emerging and rapidly progressing. Therefore, we have also added a review on the progress made in this field of research. Full article

(This article belongs to the Special Issue Molecular Regulatory Mechanisms of Membrane Trafficking)

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19 pages, 7217 KiB

Open AccessReview

The Role of TCOF1 Gene in Health and Disease: Beyond Treacher Collins Syndrome

by Małgorzata Grzanka and Agnieszka Piekiełko-Witkowska

Int. J. Mol. Sci. 2021, 22(5), 2482; https://doi.org/10.3390/ijms22052482 - 1 Mar 2021

Cited by 16 | Viewed by 6232

Abstract

The nucleoli are membrane-less nuclear substructures that govern ribosome biogenesis and participate in multiple other cellular processes such as cell cycle progression, stress sensing, and DNA damage response. The proper functioning of these organelles is ensured by specific proteins that maintain nucleolar structure [...] Read more.

The nucleoli are membrane-less nuclear substructures that govern ribosome biogenesis and participate in multiple other cellular processes such as cell cycle progression, stress sensing, and DNA damage response. The proper functioning of these organelles is ensured by specific proteins that maintain nucleolar structure and mediate key nucleolar activities. Among all nucleolar proteins, treacle encoded by TCOF1 gene emerges as one of the most crucial regulators of cellular processes. TCOF1 was initially discovered as a gene involved in the Treacher Collins syndrome, a rare genetic disorder characterized by severe craniofacial deformations. Later studies revealed that treacle regulates ribosome biogenesis, mitosis, proliferation, DNA damage response, and apoptosis. Importantly, several reports indicate that treacle is also involved in cancer development, progression, and response to therapies, and may contribute to other pathologies such as Hirschsprung disease. In this manuscript, we comprehensively review the structure, function, and the regulation of TCOF1/treacle in physiological and pathological processes. Full article

(This article belongs to the Special Issue Molecular Regulatory Mechanisms of Membrane Trafficking)

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