Cryptococcus neoformans Iron-Sulfur Protein Biogenesis Machinery Is a Novel Layer of Protection against Cu Stress

MBio
Sarela García-SantamarinaD J Thiele

Abstract

Copper (Cu) ions serve as catalytic cofactors to drive key biochemical processes, and yet Cu levels that exceed cellular homeostatic control capacity are toxic. The underlying mechanisms for Cu toxicity are poorly understood. During pulmonary infection by the fungal pathogen Cryptococcus neoformans, host alveolar macrophages compartmentalize Cu to the phagosome, and the ability to detoxify Cu is critical for its survival and virulence. Here, we report that iron-sulfur (Fe-S) clusters are critical targets of Cu toxicity in both Saccharomyces cerevisiae and C. neoformans in a manner that depends on the accessibility of Cu to the Fe-S cofactor. To respond to this Cu-dependent Fe-S stress, C. neoformans induces the transcription of mitochondrial ABC transporter Atm1, which functions in cytosolic-nuclear Fe-S protein biogenesis in response to Cu and in a manner dependent on the Cu metalloregulatory transcription factor Cuf1. As Atm1 functions in exporting an Fe-S precursor from the mitochondrial matrix to the cytosol, C. neoformans cells depleted for Atm1 are sensitive to Cu even while the Cu-detoxifying metallothionein proteins are highly expressed. We provide evidence for a previously unrecognized microbial defense mechanism to de...Continue Reading

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Citations

Apr 3, 2018·Molecular Microbiology·Sarela Garcia-SantamarinaDennis J Thiele
Jan 10, 2019·International Journal of Molecular Sciences·Chao LiChen Ding
Jan 15, 2020·Nature Chemical Biology·Sarela Garcia-SantamarinaDennis J Thiele
Jul 18, 2020·Frontiers in Microbiology·Xin LiuJianrong Shi
Nov 12, 2019·Metallomics : Integrated Biometal Science·Elizabeth W Hunsaker, Katherine J Franz
Feb 11, 2021·The Journal of Biological Chemistry·Aaron D SmithDennis J Thiele
Jan 12, 2021·Seminars in Cell & Developmental Biology·Edward M Culbertson, Valeria C Culotta
Sep 27, 2020·Biochimica Et Biophysica Acta. Molecular Cell Research·Paul A CobineScot C Leary
Oct 24, 2020·International Journal for Parasitology. Drugs and Drug Resistance·Maria GrechnikovaRobert Sutak
Dec 12, 2020·ACS Chemical Biology·Nancy WiebelhausMichael C Fitzgerald
Sep 7, 2021·Frontiers in Cellular and Infection Microbiology·Tianshu SunYingchun Xu
May 11, 2020·Ecotoxicology and Environmental Safety·Sezer OkayGülay Özcengiz
Dec 23, 2021·Science Advances·Thomas L EllinghausWerner Kühlbrandt

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Methods Mentioned

BETA
X-ray
reverse transcription-PCR
immunoprecipitation-PCR
confocal microscopy
immunoprecipitation
PCR

Software Mentioned

Multalin

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