MYO1F regulates antifungal immunity by regulating acetylation of microtubules

Abstract

Opportunistic fungal infections have become one of the leading causes of death among immunocompromised patients, resulting in an estimated 1.5 million deaths each year worldwide. The molecular mechanisms that promote host defense against fungal infections remain elusive. Here, we find that Myosin IF (MYO1F), an unconventional myosin, promotes the expression of genes that are critical for antifungal innate immune signaling and proinflammatory responses. Mechanistically, MYO1F is required for dectin-induced α-tubulin acetylation, acting as an adaptor that recruits both the adaptor AP2A1 and α-tubulin N-acetyltransferase 1 to α-tubulin; in turn, these events control the membrane-to-cytoplasm trafficking of spleen tyrosine kinase and caspase recruitment domain-containing protein 9. Myo1f-deficient mice are more susceptible than their wild-type counterparts to the lethal sequelae of systemic infection with Candida albicans. Notably, administration of Sirt2 deacetylase inhibitors, namely AGK2, AK-1, or AK-7, significantly increases the dectin-induced expression of proinflammatory genes in mouse bone marrow–derived macrophages and microglia, thereby protecting mice from both systemic and central nervous system C. albicans infections. AGK2 also promotes proinflammatory gene expression in human peripheral blood mononuclear cells after Dectin stimulation. Taken together, our findings describe a key role for MYO1F in promoting antifungal immunity by regulating the acetylation of α-tubulin and microtubules, and our findings suggest that Sirt2 deacetylase inhibitors may be developed as potential drugs for the treatment of fungal infections.

Dectin-1 Signaling Update: New Perspectives for Trained Immunity

“…In this sense, the E3 ligase TRIM31 is a crucial factor by interacting with cytoplasmic Syk to catalyze its K27-linked polyubiquitination, that promotes its plasma membrane translocation and binding to the intracellular domain of Dectin-1 ( 74 ). After phosphorylation, active Syk moves back to the cytoplasm based on cytoskeleton adaptations controlled by the unconventional myosin MYO1F ( 75 ), leading to downstream signal transduction. Notably, the stimulation of Dectin-1 by zymosan induced the phosphorylation of the phosphatase SHP-2.…”

“…Based on the seminal work by Deng et al , Raf-1 phosphorylation depends on SHP-2 in response to Dectin-1 ligands ( 76 ). However, the relevance of Myosin IF (MYO1F) in Syk-independent pathways was not explored ( 75 ). Considering the differential implication of MYO1F in PI3K/AKT/mammalian Target of Rapamycin (mTOR) activation after IFNγ/LPS stimulation ( 116 ), it would be interesting to address the role of this myosin for the Syk-independent molecular pathways triggered downstream Dectin-1, as well as for SHP-2.…”

Metabolic Signature-Based Subtypes May Pave Novel Ways for Low-Grade Glioma Prognosis and Therapy

“…LAPTM5, a protein, is preferentially expressed in immune cells ( Berberich et al, 2020 ), and could interact with the Nedd4 family of ubiquitin ligases, which played an essential role in multiple tumor initiation and progression. Finally, MYO1F functioned as an unconventional myosin ( Diquigiovanni et al, 2018 ; Sun et al, 2021 ) and promoted the expression of critical genes for antifungal innate immune signaling and proinflammatory responses.…”

Role of adaptin protein complexes in intracellular trafficking and their impact on diseases

“…It is involved in neural cell development via binding to m-Numb [66], as well as hematopoietic stem cell differentiation [67]. Furthermore, AP2 was found to play a role in the synaptic vesicle cycle pathway and related neurodegenerative diseases [68], in cell defense (e.g., in the antifungal defense mechanism by binding to MYO1F) [69] and in inhibition of HIV genomic incorporation [70]. However, this clathrin endocytosis-related subunit can also serve as a target of viral infection, for example, by being hijacked by HAdV-D37 [71] and HEV71 [72] viruses.…”

“…AP2A1 recognizes and binds to cargo proteins, clathrin, and accessory proteins, and thus plays a key role in the clathrin-dependent endocytosis process [ 63–65 ]. AP2A1 was reported to be involved in neural cell development via binding to m-Numb [ 66 ], in hematopoietic stem cell differentiation [ 67 ], in the synaptic vesicle cycle pathway and related neurodegenerative diseases [ 68 ], in cell defense (e.g., in the antifungal defense mechanism by binding to MYO1F) [ 69 ] and in inhibition of HIV genomic incorporation [ 70 ]. However, this clathrin endocytosis-related subunit can also serve as a target of viral infection, for example, by being hijacked by HAdV-D37 [ 71 ] and HEV71 [ 72 ] viruses.…”