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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 this depends on the canonical role of IRE1α in detecting misfolded proteins. 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.

SUBMITTER: McFadden MJ

PROVIDER: S-EPMC10592910 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Non-canonical activation of IRE1α during <i>Candida albicans</i> infection enhances macrophage fungicidal activity.

McFadden Michael J MJ Reynolds Mack B MB Michmerhuizen Britton C BC Ólafsson Einar B EB Anderson Faith M FM Schultz Tracey L TL O'Riordan Mary X D MXD O'Meara Teresa R TR

bioRxiv : the preprint server for biology 20240502

While the canonical function of IRE1α is to detect misfolded proteins and activate the unfolded protein response (UPR) to maintain cellular homeostasis, microbial pathogens can also activate IRE1α, which modulates innate immunity and infection outcomes. However, how infection activates IRE1α and its associated inflammatory functions have not been fully elucidated. Recognition of microbe-associated molecular patterns can activate IRE1α, but it is unclear whether this depends on protein misfolding ...[more]

PMID: 37873171

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Dataset Information

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

Publications

Non-canonical activation of IRE1α during <i>Candida albicans</i> infection enhances macrophage fungicidal activity.

Similar Datasets

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