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Non-canonical activation of IRE1α during Candida albicans infection enhances macrophage fungicidal activity

ABSTRACT: Infection by intracellular pathogens can trigger activation of the IRE1α branch of the unfolded protein response (UPR), which then modulates innate immunity and infection outcomes during bacterial or viral infection. However, the mechanisms by which infection activates IRE1α have not been fully elucidated. While recognition of microbe-associated molecular patterns can activate IRE1α, it is unclear whether the canonical role of IRE1α in detecting misfolded proteins is required for its activation. Here, we report that Candida albicans infection of macrophages results in IRE1α activation through C-type lectin receptor signaling, reinforcing a role for IRE1α as a central regulator of host responses to infection by a broad range of pathogens. However, IRE1α activation was not preceded by protein misfolding in response to either C. albicans infection or lipopolysaccharide treatment, implicating a non-canonical mode of IRE1α activation after recognition of microbial patterns. Investigation of the phenotypic consequences of IRE1α activation in macrophage antimicrobial responses revealed that IRE1α activity enhances the fungicidal activity of macrophages. Macrophages lacking IRE1α activity displayed inefficient phagolysosomal fusion, enabling C. albicans to evade fungal killing and escape the phagosome. Together, these data provide mechanistic insight for the non-canonical activation of IRE1α during infection, and reveal central roles for IRE1α in macrophage antifungal responses.

ORGANISM(S): Mus musculus

PROVIDER: GSE244303 | GEO | 2023/11/13

REPOSITORIES: GEO

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in vitro ubiquitination by E3 ligase Cbl-b

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2017-03-29 | MSV000080745 | MassIVE

in vitro ubiquitination by E3 ligase Cbl-b

2016-06-17 | PXD004256 | Pride

Transcriptional responses of primary murine macrophages to four Candida species

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2021-11-28 | GSE152700 | GEO

Tollip isoforms as key regulators of macrophage phenotype and response to LPS

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2022-12-18 | GSE199125 | GEO

Chromatin accessibility analysis of wild type bone marrow-derived macrophages in response to Anisomycin, type II interferon and the combination of them or with p38 MAPK inhibitor PH-797804 (ATAC-Seq IFNg)

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2022-12-18 | GSE199126 | GEO

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