bims-lypmec 2024-04-14 papers

Annu Rev Biochem. 2024 Apr 09.

Lysosomes are the degradative endpoints of material delivered by endocytosis and autophagy and are therefore particularly prone to damage. Membrane permeabilization or full rupture of lysosomal or late endosomal compartments is highly deleterious because it threatens cellular homeostasis and can elicit cell death and inflammatory signaling. Cells have developed a complex response to endo-lysosomal damage that largely consists of three branches. Initially, a number of repair pathways are activated to restore the integrity of the lysosomal membrane. If repair fails or if damage is too extensive, lysosomes are isolated and degraded by a form of selective autophagy termed lysophagy. Meanwhile, an mTORC1-governed signaling cascade drives biogenesis and regeneration of new lysosomal components to reestablish the full lysosomal capacity of the cell. This damage response is vital to counteract the effects of various conditions, including neurodegeneration and infection, and can constitute a critical vulnerability in cancer cells.

DOI: https://doi.org/10.1146/annurev-biochem-030222-102505

Cell Calcium. 2024 Apr 08. pii: S0143-4160(24)00045-9. [Epub ahead of print]120 102887

A novel probe to monitor lysosome-mitochondria contact sites opens up a new path to study neurodegenerative diseases.

Mai Makino, Shuhei Nakamura.

DOI: https://doi.org/10.1016/j.ceca.2024.102887

Cell Mol Life Sci. 2024 Apr 10. 81(1): 171

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

Max Zachrisson Totland, Lars Mørland Knudsen, Nikoline Lander Rasmussen, Yasufumi Omori, Vigdis Sørensen, Vilde C Wivestad Elster, Jakob Mørkved Stenersen, Mathias Larsen, Caroline Lunder Jensen, Anna A Zickfeldt Lade, Emilie Bruusgaard, Sebastian Basing, Kushtrim Kryeziu, Andreas Brech, Trond Aasen, Ragnhild A Lothe, Edward Leithe.

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.

Keywords: Cervix; Connexin; Deubiquitination; Endosome; NEDD4

DOI: https://doi.org/10.1007/s00018-024-05165-8