Morgana is a chaperone protein that is ubiquitously expressed and evolutionarily conserved from plants to mammals. As a co-chaperone of HSP90, Morgana plays a critical role in protecting cells from various stressful stimuli. Its functions are essential for embryonic development, though its physiological roles in adults remain unexplored. To better understand Morgana role in adult tissue physiology, we took advantage of mouse and Drosophila inducible Morgana knockout models. The loss of Morgana led to rapid death in both cases. In mice, this loss resulted in the accumulation of DNA damage, particularly in proliferative organs like the small intestine. The results obtained underscore the critical role of Morgana in protecting against DNA damage and supporting cell proliferation. We found that the protective function of Morgana against DNA damage is conserved in pathological conditions. Notably, Morgana expression is lost in 20% of triple-negative breast cancers (TNBC), where tumors lacking Morgana exhibit high levels of DNA damage. Our findings revealed that Morgana deficiency impairs the DNA damage response, reducing the ability of cells to detect and repair DNA double-strand breaks. Conversely, 11% of TNBCs overexpress Morgana, and cancer cells displaying high Morgana levels often release it into the extracellular milieu. We found that extracellular Morgana (eMorgana) forms a high molecular weight complex in the extracellular environment of cancer cells that promotes cell migration. This aberrant complex consists of three chaperones: HSP90, Morgana, and the histone chaperone Nucleophosmin 1 (NPM1). We highlighted that the pro-migratory function of the eMorgana complex depends on a novel and specific mechanism. Our data indicate that the eMorgana complex reorganizes the interactions among cell surface receptors, promoting integrin endocytosis and recycling. Overall, these findings reveal a pivotal role for Morgana in maintaining tissue homeostasis and its contribution to TNBC progression when dysregulated.
The Chaperone Protein Morgana in Tissue Homeostasis and Cancer: From DNA Repair to the Extracellular Space(2024 Dec 17).
The Chaperone Protein Morgana in Tissue Homeostasis and Cancer: From DNA Repair to the Extracellular Space
POGGIO, PIETRO
2024-12-17
Abstract
Morgana is a chaperone protein that is ubiquitously expressed and evolutionarily conserved from plants to mammals. As a co-chaperone of HSP90, Morgana plays a critical role in protecting cells from various stressful stimuli. Its functions are essential for embryonic development, though its physiological roles in adults remain unexplored. To better understand Morgana role in adult tissue physiology, we took advantage of mouse and Drosophila inducible Morgana knockout models. The loss of Morgana led to rapid death in both cases. In mice, this loss resulted in the accumulation of DNA damage, particularly in proliferative organs like the small intestine. The results obtained underscore the critical role of Morgana in protecting against DNA damage and supporting cell proliferation. We found that the protective function of Morgana against DNA damage is conserved in pathological conditions. Notably, Morgana expression is lost in 20% of triple-negative breast cancers (TNBC), where tumors lacking Morgana exhibit high levels of DNA damage. Our findings revealed that Morgana deficiency impairs the DNA damage response, reducing the ability of cells to detect and repair DNA double-strand breaks. Conversely, 11% of TNBCs overexpress Morgana, and cancer cells displaying high Morgana levels often release it into the extracellular milieu. We found that extracellular Morgana (eMorgana) forms a high molecular weight complex in the extracellular environment of cancer cells that promotes cell migration. This aberrant complex consists of three chaperones: HSP90, Morgana, and the histone chaperone Nucleophosmin 1 (NPM1). We highlighted that the pro-migratory function of the eMorgana complex depends on a novel and specific mechanism. Our data indicate that the eMorgana complex reorganizes the interactions among cell surface receptors, promoting integrin endocytosis and recycling. Overall, these findings reveal a pivotal role for Morgana in maintaining tissue homeostasis and its contribution to TNBC progression when dysregulated.File | Dimensione | Formato | |
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