TY - JOUR
T1 - The ER Protein Translocation Channel Subunit Sbh1 Controls Virulence of Cryptococcus neoformans
AU - Santiago-Tirado, Felipe H.
AU - Hurtaux, Thomas
AU - Geddes-McAlister, Jennifer
AU - Nguyen, Duy
AU - Helms, Volkhard
AU - Doering, Tamara L.
AU - Römisch, Karin
N1 - Publisher Copyright:
© 2023 Santiago-Tirado et al.
PY - 2023/1
Y1 - 2023/1
N2 - The fungal pathogen Cryptococcus neoformans is distinguished by a cell-wallanchored polysaccharide capsule that is critical for virulence. Biogenesis of both cell wall and capsule relies on the secretory pathway. Protein secretion begins with polypeptide translocation across the endoplasmic reticulum (ER) membrane through a highly conserved channel formed by three proteins: Sec61, Sbh1, and Sss1. Sbh1, the most divergent, contains multiple phosphorylation sites, which may allow it to regulate entry into the secretory pathway in a species- and protein-specific manner. Absence of SBH1 causes a cell-wall defect in both Saccharomyces cerevisiae and C. neoformans, although other phenotypes differ. Notably, proteomic analysis showed that when cryptococci are grown in conditions that mimic aspects of the mammalian host environment (tissue culture medium, 37°C, 5% CO2), a set of secretory and transmembrane proteins is upregulated in wild-type, but not in Dsbh1 mutant cells. The Sbh1-dependent proteins show specific features of their ER targeting sequences that likely cause them to transit less efficiently into the secretory pathway. Many also act in cell-wall biogenesis, while several are known virulence factors. Consistent with these observations, the C. neoformans Dsbh1 mutant is avirulent in a mouse infection model. We conclude that, in the context of conditions encountered during infection, Sbh1 controls the entry of virulence factors into the secretory pathway of C. neoformans, and thereby regulates fungal pathogenicity.
AB - The fungal pathogen Cryptococcus neoformans is distinguished by a cell-wallanchored polysaccharide capsule that is critical for virulence. Biogenesis of both cell wall and capsule relies on the secretory pathway. Protein secretion begins with polypeptide translocation across the endoplasmic reticulum (ER) membrane through a highly conserved channel formed by three proteins: Sec61, Sbh1, and Sss1. Sbh1, the most divergent, contains multiple phosphorylation sites, which may allow it to regulate entry into the secretory pathway in a species- and protein-specific manner. Absence of SBH1 causes a cell-wall defect in both Saccharomyces cerevisiae and C. neoformans, although other phenotypes differ. Notably, proteomic analysis showed that when cryptococci are grown in conditions that mimic aspects of the mammalian host environment (tissue culture medium, 37°C, 5% CO2), a set of secretory and transmembrane proteins is upregulated in wild-type, but not in Dsbh1 mutant cells. The Sbh1-dependent proteins show specific features of their ER targeting sequences that likely cause them to transit less efficiently into the secretory pathway. Many also act in cell-wall biogenesis, while several are known virulence factors. Consistent with these observations, the C. neoformans Dsbh1 mutant is avirulent in a mouse infection model. We conclude that, in the context of conditions encountered during infection, Sbh1 controls the entry of virulence factors into the secretory pathway of C. neoformans, and thereby regulates fungal pathogenicity.
KW - Cryptococcus neoformans
KW - Saccharomyces cerevisiae
KW - Sbh1
KW - cell wall
KW - protein translocation
KW - virulence
UR - http://www.scopus.com/inward/record.url?scp=85149154302&partnerID=8YFLogxK
U2 - 10.1128/mbio.03384-22
DO - 10.1128/mbio.03384-22
M3 - Article
C2 - 36749043
AN - SCOPUS:85149154302
SN - 2161-2129
VL - 14
JO - mBio
JF - mBio
IS - 1
ER -