The E3 ubiquitin ligase ITCH negatively regulates intercellular communication via gap junctions by targeting connexin43 for lysosomal degradation

The E3 ubiquitin ligase ITCH negatively regulates intercellular communication via gap junctions by targeting connexin43 for lysosomal degradation

Intercellular communication via gap junctions has a fundamental role in regulating cell growth and tissue homeostasis, and its dysregulation may be involved in cancer development and radio- and chemotherapy resistance. Connexin43 (Cx43) is the most ubiquitously expressed gap junction channel protein...

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Bibliographic Details
Published in:Cellular and molecular life sciences : CMLS Vol. 81; no. 1; p. 171
Main Authors: Totland, Max Zachrisson, Knudsen, Lars Mørland, Rasmussen, Nikoline Lander, Omori, Yasufumi, Sørensen, Vigdis, Elster, Vilde C. Wivestad, Stenersen, Jakob Mørkved, Larsen, Mathias, Jensen, Caroline Lunder, Zickfeldt Lade, Anna A., Bruusgaard, Emilie, Basing, Sebastian, Kryeziu, Kushtrim, Brech, Andreas, Aasen, Trond, Lothe, Ragnhild A., Leithe, Edward
Format: Journal Article
Language:English
Published: Cham Springer International Publishing 01-12-2024
Springer Nature B.V
Subjects:
Biochemistry
Biomedical and Life Sciences
Biomedicine
C-Terminus
Cancer
Cell Biology
Cell Communication
Cell interactions
Cervical cancer
Chemoresistance
Chemotherapy
Communication
Connexin 43
Connexin 43 - genetics
Connexins
Degradation
Gap Junctions
Homeostasis
Human tissues
Humans
Life Sciences
Lysosomes
Original
Original Article
Ubiquitin-protein ligase
Ubiquitin-Protein Ligases - genetics
Ubiquitination
Connexin
Cervix
Endosome
Deubiquitination
NEDD4
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Summary:Intercellular communication via gap junctions has a fundamental role in regulating cell growth and tissue homeostasis, and its dysregulation may be involved in cancer development and radio- and chemotherapy resistance. Connexin43 (Cx43) is the most ubiquitously expressed gap junction channel protein in human tissues. Emerging evidence indicates that dysregulation of the sorting of Cx43 to lysosomes is important in mediating the loss of Cx43-based gap junctions in cancer cells. However, the molecular basis underlying this process is currently poorly understood. Here, we identified the E3 ubiquitin ligase ITCH as a novel regulator of intercellular communication via gap junctions. We demonstrate that ITCH promotes loss of gap junctions in cervical cancer cells, which is associated with increased degradation of Cx43 in lysosomes. The data further indicate that ITCH interacts with and regulates Cx43 ubiquitination and that the ITCH-induced loss of Cx43-based gap junctions requires its catalytic HECT (homologous to E6-AP C-terminus) domain. The data also suggest that the ability of ITCH to efficiently promote loss of Cx43-based gap junctions and degradation of Cx43 depends on a functional PY (PPXY) motif in the C-terminal tail of Cx43. Together, these data provide new insights into the molecular basis underlying the degradation of Cx43 and have implications for the understanding of how intercellular communication via gap junctions is lost during cancer development.
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ISSN:1420-682X
1420-9071
DOI:10.1007/s00018-024-05165-8