NICKEL TOXICITY & CHOLESTEROL – SCIENCE & TECHNOLOGY
NEWS:
Researchers at the University of Georgia found that exposing mammalian and
fungal cells to nickel leads to sterol deficiency.
WHAT’S IN
THE NEWS?
Findings
in Fungal Cells
- Nickel Tolerance and ERG25: The fungal cells showed increased
tolerance to nickel when they overexpressed the ERG25 gene, which encodes
an enzyme involved in sterol biosynthesis.
- Dependency on ERG25: Cells unable to overproduce ERG25
couldn’t grow in higher nickel concentrations, indicating the gene’s role
in nickel tolerance.
Background
on Nickel and Sterols
- Nickel in Nature: Nickel is crucial for urease enzyme
activity in plants, bacteria, and fungi, though it is known to be
carcinogenic and an allergen in humans.
- Role of Sterols: Sterols contribute to cell membrane
rigidity. Cholesterol is the primary sterol in mammals, while ergosterol
serves this role in fungi.
Use of
Antifungal Drugs
- Targeting Ergosterol: Drugs like azoles and polyenes combat
fungal infections by inhibiting or binding to ergosterol, leaving
cholesterol in mammals unaffected.
- Therapeutic Relevance: This selective inhibition is what makes
antifungal drugs effective without harming host cells.
Key
Experiment on Cryptococcus neoformans
- Growth in Nickel-Rich Medium: The wild-type strain of Cryptococcus
neoformans could grow in a medium with high nickel concentrations,
indicating an unexpected tolerance.
- Role of Urease: Contrary to expectations, mutated
strains lacking urease activity survived in nickel-rich environments,
showing that urease wasn’t involved in nickel tolerance.
Discovery
of Sre1’s Role
- Mutant Screen: Researchers tested 284 C. neoformans
mutants and found that only the strain lacking sterol response element 1
(Sre1) was highly sensitive to nickel.
- Shift in Focus: This unexpected sensitivity led
researchers to focus on Sre1, which regulates sterol biosynthesis genes.
Mechanism
of Nickel Tolerance
- Conservation of SRE1: The gene encoding Sre1 is conserved
across animals. In mammals, it is known as SREBP (sterol regulatory
element-binding protein).
- Nickel Activation: In the study, nickel triggered cleavage
of SREBP in human cells, leading to reduced cholesterol, similar to its
effect on ergosterol in fungi.
ERG25 and
Nickel Tolerance
- Gene Expression Testing: Overexpression of ERG25 alone restored
nickel tolerance in Sre1 mutants, suggesting its crucial role in the
nickel response.
- Similar Effects in Mammalian Cells: After 72 hours of nickel exposure,
mammalian cells also exhibited reduced cholesterol, mirroring the effect
seen in fungal cells.
Future
Research Directions
- Questions for Further Study: Key questions include whether ERG25
homologues in other fungi can restore nickel tolerance in mutants and
whether ERG25’s sterol biosynthesis function is essential for nickel
tolerance.
- Potential for New Treatments: Understanding how ERG25 mediates nickel
tolerance could lead to novel antifungal therapies by blocking the
diversion of the protein from sterol synthesis to nickel tolerance.
Conclusion
- Implications: The findings highlight a surprising
connection between metal toxicity and sterol biosynthesis, with potential
for new antifungal drug targets based on this pathway.
Source: https://www.thehindu.com/sci-tech/science/unexpected-link-between-nickel-toxicity-cholesterol-levels-found/article68827699.ece