Endocytosis of Connexin 36 is Mediated by Interaction with Caveolin-1

Kotova, Anna; Timonina, Ksenia; Zoidl, Georg

doi:10.3390/ijms21155401

Cited by 11 publications

(6 citation statements)

References 75 publications

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“…In addition, Eps15 can couple ubiquitinated cargo to clathrin-independent internalization [ 54 ]. Furthermore, Cx36 has been shown to interact with caveolin-1 in a calcium-regulated manner, and it has been suggested to play a role in the fast, steady-state endocytosis of Cx36 [ 55 ]. Hence, it is possible that connexins 46, 26, 31, and 40.1 (and potentially other connexins) use Eps15 (or another adaptor) and K63-based polyubiquitination or even a caveolin-dependent pathway (or another endocytic pathway) for endocytosis.…”

Section: Discussionmentioning

confidence: 99%

Endocytosis and Endocytic Motifs across the Connexin Gene Family

Fisher

Falk

2023

IJMS

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Proteins fated to be internalized by clathrin-mediated endocytosis require an endocytic motif, where AP-2 or another adaptor protein can bind and recruit clathrin. Tyrosine and di-leucine-based sorting signals are such canonical motifs. Connexin 43 (Cx43) has three canonical tyrosine-based endocytic motifs, two of which have been previously shown to recruit clathrin and mediate its endocytosis. In addition, di-leucine-based motifs have been characterized in the Cx32 C-terminal domain and shown to mediate its endocytosis. Here, we examined the amino acid sequences of all 21 human connexins to identify endocytic motifs across the connexin gene family. We find that although there is limited conservation of endocytic motifs between connexins, 14 of the 21 human connexins contain one or more canonical tyrosine or di-leucine-based endocytic motif in their C-terminal or intracellular loop domain. Three connexins contain non-canonical (modified) di-leucine motifs. However, four connexins (Cx25, Cx26, Cx31, and Cx40.1) do not harbor any recognizable endocytic motif. Interestingly, live cell time-lapse imaging of different GFP-tagged connexins that either contain or do not contain recognizable endocytic motifs readily undergo endocytosis, forming clearly identifiable annular gap junctions when expressed in HeLa cells. How connexins without defined endocytic motifs are endocytosed is currently not known. Our results demonstrate that an array of endocytic motifs exists in the connexin gene family. Further analysis will establish whether the sites we identified in this in silico analysis are legitimate endocytic motifs.

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Section: Discussionmentioning

confidence: 99%

Endocytosis and Endocytic Motifs across the Connexin Gene Family

Fisher

Falk

2023

IJMS

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“…The signaling pathway consists of ionotropic NMDA receptors, SFK, and Panx1 and is distinct from protein interactions that we and others have previously reported involving Cx36. These include binding to Ca 2+ loaded CaM 34 , which mainly occurs at the ER/Golgi complex 18 , the interaction with tubulin facilitating microtubuledependent transport to the GJP 24 , or the removal of Cx36 from the GJP by binding to caveolin-1 35 . Our present interpretation is that these known interactions primarily contribute to on-demand transport to the GJP and endocytosis of Cx36.…”

Section: Discussionmentioning

confidence: 99%

Convergent NMDA receptor—Pannexin1 signaling pathways regulate the interaction of CaMKII with Connexin-36

et al. 2021

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Ca2+/calmodulin-dependent protein kinase II (CaMKII) binding and phosphorylation of mammalian connexin-36 (Cx36) potentiate electrical coupling. To explain the molecular mechanism of how Cx36 modifies plasticity at gap junctions, we investigated the roles of ionotropic N-methyl-D-aspartate receptors and pannexin1 (Panx1) channels in regulating Cx36 binding to CaMKII. Pharmacological interference and site-directed mutagenesis of protein interaction sites shows that NMDA receptor activation opens Cx36 channels, causing the Cx36- CaMKII binding complex to adopt a compact conformation. Ectopic Panx1 expression in a Panx1 knock-down cell line is required to restore CaMKII mediated opening of Cx36. Furthermore, blocking of Src-family kinase activation of Panx1 is sufficient to prevent the opening of Cx36 channels. Our research demonstrates that the efficacy of Cx36 channels requires convergent calcium-dependent signaling processes in which activation of ionotropic N-methyl-D-aspartate receptor, Src-family kinase, and Pannexin1 open Cx36. Our results add to the best of our knowledge a new twist to mounting evidence for molecular communication between these core components of electrical and chemical synapses.

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“…The expression of Cav-1, which has been reported to interact and co-localize with Dsg3 and is associated with lipid raftmediated endocytosis, 13,14 was examined to investigate the possible mechanism by which IL-37 inhibits Dsg3 endocytosis. The mRNA level of Cav-1 was significantly decreased in the anti-Dsg3 group as compared to the control group, while IL-37 significantly increased Cav-1 mRNA level (Figure 2a, p < 0.05).…”

Section: Interleukin 37 Upregulates Cav-1 Expression and Increases Th...mentioning

confidence: 99%

Interleukin‐37 inhibits desmoglein‐3 endocytosis and keratinocyte dissociation via upregulation of Caveolin‐1 and inhibition of the STAT3 pathway

Liang,

Hu,

Mao

et al. 2023

Acad Dermatol Venereol

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BackgroundPemphigus vulgaris (PV) is a potentially fatal autoimmune bullous disease primarily caused by acantholysis of keratinocytes attributed to pathogenic desmoglein‐3 (Dsg3) autoantibodies. Interleukin‐37 (IL‐37) reportedly plays important roles in a variety of autoimmune diseases, but its role in PV is not clear.ObjectivesTo investigate whether IL‐37 plays a role in the occurrence and progression of PV.MethodsHaCaT keratinocytes were stimulated with anti‐Dsg3 antibody to establish an in vitro PV model, which was defined as anti‐Dsg3 group. Cells incubated with medium without anti‐Dsg3 treatment were used as control. IL‐37 was cultured with these cells infected with or without lentiviral vector shRNA‐Caveolin‐1 (sh‐Cav‐1‐LV). Cell dissociation assay and immunocytofluorescence were performed to assess keratinocyte dissociation, keratin retraction and Dsg3 endocytosis. Real‐time PCR was used to detect the mRNA level of Cav‐1, and western blot was used to determine the protein expression of Cav‐1, Dsg3, STAT3 and phosphorylated‐STAT3 (p‐STAT3).ResultsThe anti‐Dsg3 group showed more cell debris, increased keratin retraction, increased Dsg3 endocytosis, reduced Cav‐1 expression and co‐localization than the control group, while IL‐37 treatment neutralized all of these changes. Interestingly, Cav‐1 knockdown supressed the inhibitory effect of IL‐37 on keratinocyte dissociation and Dsg3 internalization. The protein expression of p‐STAT3 was increased in keratinocytes of the PV model but decreased by IL‐37. Re‐activation of the STAT3 pathway by colivelin supressed the inhibitory effect of IL‐37 on keratinocyte dissociation and Dsg3 internalization, along with upregulation of Cav‐1 and Dsg3.ConclusionsIL‐37 inhibited keratinocyte dissociation and Dsg3 endocytosis in an in vitro PV model through the upregulating Cav‐1 and inhibiting STAT3 pathway.

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Endocytosis of Connexin 36 is Mediated by Interaction with Caveolin-1

Cited by 11 publications

References 75 publications

Endocytosis and Endocytic Motifs across the Connexin Gene Family

Endocytosis and Endocytic Motifs across the Connexin Gene Family

Convergent NMDA receptor—Pannexin1 signaling pathways regulate the interaction of CaMKII with Connexin-36

Interleukin‐37 inhibits desmoglein‐3 endocytosis and keratinocyte dissociation via upregulation of Caveolin‐1 and inhibition of the STAT3 pathway

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