Abnormal sterol-induced cell wall glucan deficiency in yeast is due to impaired glucan synthase transport to the plasma membrane

Author(s)

Roxana Gutierrez-Armijos, L. ^[1] ; Sussmann, Rodrigo A. C. ^{[1, 2]} ; Silber, Ariel M. ^[1] ; Cortez, Mauro ^[1] ; Hernandez, Agustin ^{[3, 1]}

Affiliation

^[1] Univ Sao Paulo, Dept Parasitol, Inst Ciencias Biomed, Sao Paulo, SP - Brazil

^[2] Univ Fed Sul Bahia, Ctr Formacao Ciencias Ambientais, Porto Seguro, BA - Brazil

^[3] Univ Fed Sao Carlos, Dept Genet & Evolucao, Sao Carlos, SP - Brazil

• Document type: Journal article
• Source: Biochemical Journal; v. 477, n. 24, p. 4729-4744, DEC 2020.
• Web of Science Citations: 0

Abstract

Abnormal sterols disrupt cellular functions through yet unclear mechanisms. In Saccharomyces cerevisiae, accumulation of Delta(8)-sterols, the same type of sterols observed in patients of Conradi-Hunermann-Happle syndrome or in fungi after amine fungicide treatment, leads to cell wall weakness. We have studied the influence of Delta(8)-sterols on the activity of glucan synthase I, the protein synthetizing the main polymer in fungal cell walls, its regulation by the Cell Wall Integrity (CWI) pathway, and its transport from the endoplasmic reticulum to the plasma membrane. We ascertained that the catalytic characteristics were mostly unaffected by the presence of abnormal sterols but the enzyme was partially retained in the endoplasmic reticulum, leading to glucan deficit at the cell wall. Furthermore, we observed that glucan synthase I traveled through an unconventional exocytic route to the plasma membrane that is associated with low density intracellular membranes. Also, we found out that the CWI pathway remained inactive despite low glucan levels at the cell wall. Taken together, these data suggest that Delta(8)-sterols affect cell walls by inhibiting unconventional secretion of proteins leading to retention and degradation of glucan synthase I, while the compensatory CWI pathway is unable to activate. These results could be instrumental to understand defects of bone development in cholesterol biosynthesis disorders and fungicide mechanisms of action. (AU)

• FAPESP's process: 14/10443-0 - Mechanisms and consequences of intracellular traffic impairment by 8- and 14-dehydrosterols in fungal parasite models
• Grantee: Agustín Hernández López
• Support Opportunities: Research Grants - Young Investigators Grants
• FAPESP's process: 16/06034-2 - The biological role of amino acids and their metabolites in Trypanosoma cruzi
• Grantee: Ariel Mariano Silber
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 12/24105-3 - Immunobiology of Leishmania spp.: study of the role of CD200 and biogenesis of parasitophorous vacuole in fagocitic cells infected by Leishmania
• Grantee: Mauro Javier Cortez Véliz
• Support Opportunities: Research Grants - Young Investigators Grants