{
  "abstract": "As a master of host-cell reprogramming, Toxoplasma gondii (T. gondii) tachyzoites manipulate diverse signaling networks to establish a niche permissive for long-term infection. While the parasite’s subversion of canonical NF-κB signaling (p65/p50) is well established, how infection impacts the non-canonical NF-κB pathway has been largely unexplored. Here, we report that T. gondii infection induces nuclear accumulation of the non-canonical NF-κB subunits RelB and p52 in both human and murine fibroblasts. This response is conserved across both type I and type II parasite genetic backgrounds. We demonstrate that this reprogramming is dependent on the MYR1-mediated export of dense granule effectors. Mechanistically, T. gondii infection drives the depletion of the negative regulator TRAF3, leading to the stabilization of NF-κB-inducing kinase (NIK), phosphorylation of p100, and its subsequent processing into p52. Utilizing a panel of combinatorial knockout parasites, we reveal that no single effector is responsible for this phenotype. Instead, a suite of eight MYR1-dependent effectors, IST, NSM, HCE1/TEEGR, GRA16, GRA18, GRA24, GRA28, and GRA84, functions through a collaborative, additive network to drive most of the non-canonical response. These findings highlight a distributed regulatory strategy used by the parasite to overcome host transcriptional robustness and shape host signaling.\n\nIMPORTANCE: Toxoplasma gondii infects nearly one-third of the global population and establishes infection by extensively rewiring host immune signaling. While decades of work have focused on how the parasite modulates canonical NF-κB activity, whether it also engages the alternative, non-canonical arm of this pathway has remained unclear. Here, we show that T. gondii tachyzoites activate non-canonical NF-κB signaling, driving nuclear accumulation of RelB/p52 through MYR1-dependent effector export. Unexpectedly, no single effector is responsible. Instead, eight secreted proteins act cooperatively to enable NIK stabilization and engage the non-canonical NF-κB cascade, revealing a networked mode of immune control. This discovery highlights a regulatory logic evolved by the parasite to overcome host transcriptional robustness. Together, these findings identify non-canonical NF-κB activation as a new axis of host-parasite interaction and expand our understanding of how T. gondii reprograms central immune signaling circuits through multi-effector networks.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Infectious Diseases, University of Georgia, Athens, Georgia, USA",
    "Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, Georgia, USA",
    "Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, USA",
    "Department of Cellular Biology, University of Georgia, Athens, Georgia, USA"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 5,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Kenna Berg",
      "orcid": "0009-0007-4814-2015"
    },
    {
      "affs": [
        2
      ],
      "name": "Michael W. Panas",
      "orcid": "0000-0002-2973-736X"
    },
    {
      "affs": [
        1,
        3
      ],
      "name": "Samarchith P. Kurup"
    },
    {
      "affs": [
        2
      ],
      "name": "John C. Boothroyd",
      "orcid": "0000-0001-9719-745X"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Alex Rosenberg",
      "orcid": "0000-0001-9672-1360"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/4gsrzd0hebcdr.bib",
  "cited_by": 1,
  "doi": "10.1128/mbio.01652-26",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13712946/",
  "id": "4gsrzd0hebcdr",
  "issns": [
    "2150-7511"
  ],
  "landing_url": "https://doi.org/10.1128/mbio.01652-26",
  "language": "en",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Research Article"
    ],
    [
      "openalex",
      "2405|Toxoplasma gondii Research Studies"
    ]
  ],
  "openalex": "W7204527759",
  "pdf_url": null,
  "pmcid": "PMC13712946",
  "pmid": "42663465",
  "published": "2026-08-28",
  "publisher": "American Society for Microbiology (ASM)",
  "ris": "https://research.draconitic.com/paper/4gsrzd0hebcdr.ris",
  "sources": [
    {
      "first_seen": "2026-10-31T12:23:26Z",
      "native_id": "PMC13712946",
      "source": "pmc",
      "url": "https://doi.org/10.1128/mbio.01652-26"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:2405|Toxoplasma gondii Research Studies",
      "subfield": "microbiology"
    }
  ],
  "title": "A suite of eight Toxoplasma gondii effectors cooperates to activate the non-canonical NF-κB pathway",
  "title_text": "A suite of eight Toxoplasma gondii effectors cooperates to activate the non-canonical NF-κB pathway",
  "type": "peer-reviewed",
  "updated_at": "2026-10-31T12:23:26Z",
  "url": "https://research.draconitic.com/paper/4gsrzd0hebcdr",
  "venue": "mBio",
  "versions": []
}