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Keratinocyte differentiation promotes ER stress-dependent lysosome biogenesis.

Identifieur interne : 000317 ( Main/Curation ); précédent : 000316; suivant : 000318

Keratinocyte differentiation promotes ER stress-dependent lysosome biogenesis.

Auteurs : Sarmistha Mahanty [Inde] ; Shruthi Shirur Dakappa [Inde] ; Rezwan Shariff [Inde] ; Saloni Patel [Inde] ; Mruthyunjaya Mathapathi Swamy [Inde] ; Amitabha Majumdar [Inde] ; Subba Rao Gangi Setty [Inde]

Source :

RBID : pubmed:30890691

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English descriptors

Abstract

Keratinocytes maintain epidermal integrity through cellular differentiation. This process enhances intraorganelle digestion in keratinocytes to sustain nutritional and calcium-ionic stresses observed in upper skin layers. However, the molecular mechanisms governing keratinocyte differentiation and concomitant increase in lysosomal function is poorly understood. Here, by using primary neonatal human epidermal keratinocytes, we identified the molecular link between signaling pathways and cellular differentiation/lysosome biogenesis. Incubation of keratinocytes with CaCl2 induces differentiation with increased cell size and early differentiation markers. Further, differentiated keratinocytes display enhanced lysosome biogenesis generated through ATF6-dependent ER stress signaling, but independent of mTOR-MiT/TFE pathway. In contrast, chemical inhibition of mTORC1 accelerates calcium-induced keratinocyte differentiation, suggesting that activation of autophagy promotes the differentiation process. Moreover, differentiation of keratinocytes results in lysosome dispersion and Golgi fragmentation, and the peripheral lysosomes showed colocalization with Golgi-tethering proteins, suggesting that these organelles possibly derived from Golgi. In line, inhibition of Golgi function, but not the depletion of Golgi-tethers or altered lysosomal acidity, abolishes keratinocyte differentiation and lysosome biogenesis. Thus, ER stress regulates lysosome biogenesis and keratinocyte differentiation to maintain epidermal homeostasis.

DOI: 10.1038/s41419-019-1478-4
PubMed: 30890691
PubMed Central: PMC6425001

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<term>ADP-Ribosylation Factors (MeSH)</term>
<term>Activating Transcription Factor 6 (genetics)</term>
<term>Activating Transcription Factor 6 (metabolism)</term>
<term>Autophagy (drug effects)</term>
<term>Autophagy (genetics)</term>
<term>Basic Helix-Loop-Helix Leucine Zipper Transcription Factors (genetics)</term>
<term>Basic Helix-Loop-Helix Leucine Zipper Transcription Factors (metabolism)</term>
<term>Calcium (pharmacology)</term>
<term>Cell Differentiation (MeSH)</term>
<term>Endoplasmic Reticulum (metabolism)</term>
<term>Endoplasmic Reticulum Stress (drug effects)</term>
<term>Endoplasmic Reticulum Stress (physiology)</term>
<term>Epidermal Cells (cytology)</term>
<term>Epidermal Cells (metabolism)</term>
<term>Golgi Apparatus (drug effects)</term>
<term>Golgi Apparatus (metabolism)</term>
<term>Humans (MeSH)</term>
<term>Keratinocytes (cytology)</term>
<term>Keratinocytes (drug effects)</term>
<term>Keratinocytes (metabolism)</term>
<term>Lysosomes (enzymology)</term>
<term>Lysosomes (metabolism)</term>
<term>Mechanistic Target of Rapamycin Complex 1 (antagonists & inhibitors)</term>
<term>Mechanistic Target of Rapamycin Complex 1 (genetics)</term>
<term>Mechanistic Target of Rapamycin Complex 1 (metabolism)</term>
<term>Microphthalmia-Associated Transcription Factor (genetics)</term>
<term>Microphthalmia-Associated Transcription Factor (metabolism)</term>
<term>Signal Transduction (genetics)</term>
<term>Skin (cytology)</term>
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<term>Appareil de Golgi (métabolisme)</term>
<term>Autophagie (effets des médicaments et des substances chimiques)</term>
<term>Autophagie (génétique)</term>
<term>Calcium (pharmacologie)</term>
<term>Cellules épidermiques (cytologie)</term>
<term>Cellules épidermiques (métabolisme)</term>
<term>Complexe-1 cible mécanistique de la rapamycine (antagonistes et inhibiteurs)</term>
<term>Complexe-1 cible mécanistique de la rapamycine (génétique)</term>
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<term>Différenciation cellulaire (MeSH)</term>
<term>Facteur de transcription ATF-6 (génétique)</term>
<term>Facteur de transcription ATF-6 (métabolisme)</term>
<term>Facteur de transcription associé à la microphtalmie (génétique)</term>
<term>Facteur de transcription associé à la microphtalmie (métabolisme)</term>
<term>Facteurs d'ADP-ribosylation (MeSH)</term>
<term>Facteurs de transcription à motifs basiques hélice-boucle-hélice et à glissière à leucines (génétique)</term>
<term>Facteurs de transcription à motifs basiques hélice-boucle-hélice et à glissière à leucines (métabolisme)</term>
<term>Humains (MeSH)</term>
<term>Kératinocytes (cytologie)</term>
<term>Kératinocytes (effets des médicaments et des substances chimiques)</term>
<term>Kératinocytes (métabolisme)</term>
<term>Lysosomes (enzymologie)</term>
<term>Lysosomes (métabolisme)</term>
<term>Peau (cytologie)</term>
<term>Peau (métabolisme)</term>
<term>Réticulum endoplasmique (métabolisme)</term>
<term>Stress du réticulum endoplasmique (effets des médicaments et des substances chimiques)</term>
<term>Stress du réticulum endoplasmique (physiologie)</term>
<term>Transduction du signal (génétique)</term>
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<term>Mechanistic Target of Rapamycin Complex 1</term>
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<term>Activating Transcription Factor 6</term>
<term>Basic Helix-Loop-Helix Leucine Zipper Transcription Factors</term>
<term>Mechanistic Target of Rapamycin Complex 1</term>
<term>Microphthalmia-Associated Transcription Factor</term>
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<term>Activating Transcription Factor 6</term>
<term>Basic Helix-Loop-Helix Leucine Zipper Transcription Factors</term>
<term>Mechanistic Target of Rapamycin Complex 1</term>
<term>Microphthalmia-Associated Transcription Factor</term>
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<term>Calcium</term>
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<keywords scheme="MESH" type="chemical" xml:lang="en">
<term>ADP-Ribosylation Factors</term>
</keywords>
<keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr">
<term>Complexe-1 cible mécanistique de la rapamycine</term>
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<keywords scheme="MESH" qualifier="cytologie" xml:lang="fr">
<term>Cellules épidermiques</term>
<term>Kératinocytes</term>
<term>Peau</term>
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<keywords scheme="MESH" qualifier="cytology" xml:lang="en">
<term>Epidermal Cells</term>
<term>Keratinocytes</term>
<term>Skin</term>
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<keywords scheme="MESH" qualifier="drug effects" xml:lang="en">
<term>Autophagy</term>
<term>Endoplasmic Reticulum Stress</term>
<term>Golgi Apparatus</term>
<term>Keratinocytes</term>
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<term>Appareil de Golgi</term>
<term>Autophagie</term>
<term>Kératinocytes</term>
<term>Stress du réticulum endoplasmique</term>
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<term>Lysosomes</term>
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<term>Lysosomes</term>
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<term>Autophagy</term>
<term>Signal Transduction</term>
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<term>Autophagie</term>
<term>Complexe-1 cible mécanistique de la rapamycine</term>
<term>Facteur de transcription ATF-6</term>
<term>Facteur de transcription associé à la microphtalmie</term>
<term>Facteurs de transcription à motifs basiques hélice-boucle-hélice et à glissière à leucines</term>
<term>Transduction du signal</term>
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<term>Endoplasmic Reticulum</term>
<term>Epidermal Cells</term>
<term>Golgi Apparatus</term>
<term>Keratinocytes</term>
<term>Lysosomes</term>
<term>Skin</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr">
<term>Appareil de Golgi</term>
<term>Cellules épidermiques</term>
<term>Complexe-1 cible mécanistique de la rapamycine</term>
<term>Facteur de transcription ATF-6</term>
<term>Facteur de transcription associé à la microphtalmie</term>
<term>Facteurs de transcription à motifs basiques hélice-boucle-hélice et à glissière à leucines</term>
<term>Kératinocytes</term>
<term>Lysosomes</term>
<term>Peau</term>
<term>Réticulum endoplasmique</term>
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<term>Calcium</term>
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<term>Endoplasmic Reticulum Stress</term>
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<term>Cell Differentiation</term>
<term>Humans</term>
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<keywords scheme="MESH" xml:lang="fr">
<term>Différenciation cellulaire</term>
<term>Facteurs d'ADP-ribosylation</term>
<term>Humains</term>
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<div type="abstract" xml:lang="en">Keratinocytes maintain epidermal integrity through cellular differentiation. This process enhances intraorganelle digestion in keratinocytes to sustain nutritional and calcium-ionic stresses observed in upper skin layers. However, the molecular mechanisms governing keratinocyte differentiation and concomitant increase in lysosomal function is poorly understood. Here, by using primary neonatal human epidermal keratinocytes, we identified the molecular link between signaling pathways and cellular differentiation/lysosome biogenesis. Incubation of keratinocytes with CaCl
<sub>2</sub>
induces differentiation with increased cell size and early differentiation markers. Further, differentiated keratinocytes display enhanced lysosome biogenesis generated through ATF6-dependent ER stress signaling, but independent of mTOR-MiT/TFE pathway. In contrast, chemical inhibition of mTORC1 accelerates calcium-induced keratinocyte differentiation, suggesting that activation of autophagy promotes the differentiation process. Moreover, differentiation of keratinocytes results in lysosome dispersion and Golgi fragmentation, and the peripheral lysosomes showed colocalization with Golgi-tethering proteins, suggesting that these organelles possibly derived from Golgi. In line, inhibition of Golgi function, but not the depletion of Golgi-tethers or altered lysosomal acidity, abolishes keratinocyte differentiation and lysosome biogenesis. Thus, ER stress regulates lysosome biogenesis and keratinocyte differentiation to maintain epidermal homeostasis.</div>
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<sub>2</sub>
induces differentiation with increased cell size and early differentiation markers. Further, differentiated keratinocytes display enhanced lysosome biogenesis generated through ATF6-dependent ER stress signaling, but independent of mTOR-MiT/TFE pathway. In contrast, chemical inhibition of mTORC1 accelerates calcium-induced keratinocyte differentiation, suggesting that activation of autophagy promotes the differentiation process. Moreover, differentiation of keratinocytes results in lysosome dispersion and Golgi fragmentation, and the peripheral lysosomes showed colocalization with Golgi-tethering proteins, suggesting that these organelles possibly derived from Golgi. In line, inhibition of Golgi function, but not the depletion of Golgi-tethers or altered lysosomal acidity, abolishes keratinocyte differentiation and lysosome biogenesis. Thus, ER stress regulates lysosome biogenesis and keratinocyte differentiation to maintain epidermal homeostasis.</AbstractText>
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<NameOfSubstance UI="D000076222">Mechanistic Target of Rapamycin Complex 1</NameOfSubstance>
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<Chemical>
<RegistryNumber>EC 3.6.5.2</RegistryNumber>
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<Chemical>
<RegistryNumber>SY7Q814VUP</RegistryNumber>
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<CitationSubset>IM</CitationSubset>
<CommentsCorrectionsList>
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<RefSource>Cell Death Dis. 2019 Oct 3;10(10):740</RefSource>
<PMID Version="1">31582726</PMID>
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<MeshHeadingList>
<MeshHeading>
<DescriptorName UI="D020727" MajorTopicYN="N">ADP-Ribosylation Factors</DescriptorName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D051702" MajorTopicYN="N">Activating Transcription Factor 6</DescriptorName>
<QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D001343" MajorTopicYN="N">Autophagy</DescriptorName>
<QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName>
<QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D051778" MajorTopicYN="N">Basic Helix-Loop-Helix Leucine Zipper Transcription Factors</DescriptorName>
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<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
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<MeshHeading>
<DescriptorName UI="D002118" MajorTopicYN="N">Calcium</DescriptorName>
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<MeshHeading>
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<MeshHeading>
<DescriptorName UI="D059865" MajorTopicYN="N">Endoplasmic Reticulum Stress</DescriptorName>
<QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName>
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<MeshHeading>
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<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
</MeshHeading>
<MeshHeading>
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<QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D015603" MajorTopicYN="N">Keratinocytes</DescriptorName>
<QualifierName UI="Q000166" MajorTopicYN="N">cytology</QualifierName>
<QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D008247" MajorTopicYN="N">Lysosomes</DescriptorName>
<QualifierName UI="Q000201" MajorTopicYN="N">enzymology</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D000076222" MajorTopicYN="N">Mechanistic Target of Rapamycin Complex 1</DescriptorName>
<QualifierName UI="Q000037" MajorTopicYN="N">antagonists & inhibitors</QualifierName>
<QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D051739" MajorTopicYN="N">Microphthalmia-Associated Transcription Factor</DescriptorName>
<QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D015398" MajorTopicYN="N">Signal Transduction</DescriptorName>
<QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D012867" MajorTopicYN="N">Skin</DescriptorName>
<QualifierName UI="Q000166" MajorTopicYN="N">cytology</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
</MeshHeading>
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<PubMedPubDate PubStatus="received">
<Year>2018</Year>
<Month>09</Month>
<Day>05</Day>
</PubMedPubDate>
<PubMedPubDate PubStatus="accepted">
<Year>2019</Year>
<Month>02</Month>
<Day>13</Day>
</PubMedPubDate>
<PubMedPubDate PubStatus="revised">
<Year>2019</Year>
<Month>02</Month>
<Day>12</Day>
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<PubMedPubDate PubStatus="entrez">
<Year>2019</Year>
<Month>3</Month>
<Day>21</Day>
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<PubMedPubDate PubStatus="pubmed">
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<Month>3</Month>
<Day>21</Day>
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<PubMedPubDate PubStatus="medline">
<Year>2020</Year>
<Month>5</Month>
<Day>16</Day>
<Hour>6</Hour>
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<PublicationStatus>epublish</PublicationStatus>
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<ArticleId IdType="pubmed">30890691</ArticleId>
<ArticleId IdType="doi">10.1038/s41419-019-1478-4</ArticleId>
<ArticleId IdType="pii">10.1038/s41419-019-1478-4</ArticleId>
<ArticleId IdType="pmc">PMC6425001</ArticleId>
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Data generation: Thu Nov 19 21:55:41 2020. Site generation: Thu Nov 19 22:00:39 2020