Biology subjects

Alto, N.

Publications and source records attributed to Alto, N..

3 recordsLinked to original sources

bioRxiv2026

Intracellular pathogen targeting by IL32 elicits cell-autonomous immunity

Interferon-{gamma} safeguards humans against intracellular pathogens, yet how most interferon-stimulated genes protect host cells, and how human-adapted pathogens evade these defenses is unclear1,2. Here, we discover a potent immune surveillance and effector circuit executed by an intracellularly acting cytokine, IL32, that targets and restricts phylogenetically distinct vacuolar pathogens, including the bacterium Chlamydia and the microsporidian Encephalitozoon. Quantitative proteomics coupled to a tailored CRISPR screen, uncovered components of the cysteine/Arg N-degron pathway3 that modify IL32 through oxidation-dependent arginylation, thereby enabling the recruitment of the autophagy machinery to pathogen-containing vacuoles. A forward genetics screen in Chlamydia trachomatis, the leading cause of sexually transmitted bacterial infection, identified the secreted virulence factor IncS as an evasion factor that blocks IL32 targeting and shields this human pathogen from xenophagy. These findings establish an IL32-dependent intracellular sensing mechanism linking IFN{gamma} signaling to N-degron-mediated xenophagy, revealing a broadly relevant axis of human host-pathogen conflict.

immunology↗

bioRxiv2025

The CCC complex directs phagosomal maturation and bactericidal activity in macrophages through PI(3)P regulation

The evolutionarily conserved COMMD/CCDC22/CCDC93 (CCC) complex regulates endolysosomal function and is required for effective antibacterial immunity. However, the mechanisms linking the CCC complex to macrophage function remain poorly understood. Using bone marrow-derived macrophages, we found that CCC deficiency impaired bacterial clearance and disrupted phagosome maturation, as evidenced by defective phagosomal membrane remodeling, reduced phagosome-endoplasmic reticulum contacts, and impaired phagosome-lysosome fusion. These defects were independent of the CCC complex interaction partner, Retriever. CCC-deficient macrophages exhibited excessive phosphatidylinositol 3-phosphate (PI(3)P) accumulation on phagosomal membranes due to markedly reduced recruitment of the PI(3)P phosphatase MTMR2. Restoration of normal PI(3)P levels rescued bactericidal activity, establishing aberrant PI(3)P regulation as the principal defect affecting CCC-deficient macrophages. These findings identify a previously unrecognized Retriever-independent function of the CCC complex in regulating PI(3)P dynamics during phagosome maturation, a process essential for efficient bacterial clearance and innate immune defense.

cell biology↗

bioRxiv2021

ADAP1 promotes latent HIV-1 reactivation by selectively tuning a T cell signaling-transcriptional axis

Immune stimulation fuels cell signaling-transcriptional programs inducing biological responses to eliminate virus-infected cells. Yet, retroviruses that integrate into host cell chromatin, such as HIV-1, co-opt these programs to switch between latent and reactivated states; however, the regulatory mechanisms are still unfolding. Here, we implemented a functional screen leveraging HIV-1s dependence on CD4+ T cell signaling-transcriptional programs and discovered ADAP1 is an undescribed modulator of HIV-1 proviral fate. Specifically, we report ADAP1 (ArfGAP with dual PH domain-containing protein 1), a previously thought neuronal-restricted factor, is an amplifier of select T cell signaling programs. Using complementary biochemical and cellular assays, we demonstrate ADAP1 inducibly interacts with the immune signalosome to directly stimulate KRAS GTPase activity thereby augmenting T cell signaling through targeted activation of the ERK-AP-1 axis. Single cell transcriptomics analysis revealed loss of ADAP1 function blunts gene programs upon T cell stimulation consequently dampening latent HIV-1 reactivation. Our combined experimental approach defines ADAP1 as an unexpected tuner of T cell programs co-opted by HIV-1 for latency escape.

microbiology↗