UCLA researchers in the Department of Microbiology, Immunology, and Molecular Genetics have developed methods to target TOM70, a mitochondrial outer membrane protein, to selectively modulate innate immune signaling and control pathological or protective immune responses across a range of clinical conditions.
BACKGROUND: Innate immune detection of viral and endogenous nucleic acids is mediated by RIG-I-like receptors (RLRs), which activate the mitochondrial antiviral signaling protein MAVS to induce type. Interferons (IFNs) and pro-inflammatory cytokines. While MAVS signaling is essential for host defense against RNA viruses and contributes to antitumor immunity and vaccine responses, chronic or inappropriate MAVS activation drives pathology in autoimmune or autoinflammatory diseases, including systemic lupus erythematosus, Aicardi-Goutiéres syndrome, and type I diabetes. Persistent MAVS signaling has also been implicated in neuroinflammation, neurodegeneration, and tumor-promoting inflammatory microenvironments. Despite its central role in immune signaling, MAVS has proven difficult to target therapeutically due to its rapid activation, prion-like aggregation, and lack of druggable domains. Thus, there is a critical unmet need for therapeutic strategies that can safely and selectively modulate MAVS-dependent immune response without directly targeting MAVS itself.
INNOVATION: UCLA researchers led by Dr. Lena Pernas have identified TOM70 (translocase of the outer mitochondrial membrane 70) as an essential and druggable downstream mediator of MAVS-dependent immune signaling. Unlike MAVS, TOM70 is a tractable mitochondrial protein that enables indirect yet effective modulation of innate immune responses. This technology includes a prototype-protein based inhibitor of TOM70, as well as a platform for discovering small-molecule modulators (both inhibitors and agonists) of TOM70 mediated immune signaling. Researchers have also made the discovery that TOM70 regulates type II interferon signaling, which expands its immunological role beyond MAVS-associated type I interferon induction. Together, these advances establish TOM70 as a central regulatory node that links mitochondrial signaling to innate and adaptive immunity and provide potential for therapeutic immune modulation.
POTENTIAL APPLICATIONS:
- Platform for the identification of small molecule agonists or inhibitors of TOM70-mediated immune signaling
- TOM70 inhibitors to treat autoimmune disease, chronic inflammation, or neurodegeneration
- TOM70 agonists or stabilizers as antiviral or anticancer agents
- Combination therapies with cancer checkpoint inhibitors
- Combination therapies with antiviral drugs
- Vaccine adjuvant development
ADVANTAGES:
- Targets druggable regulator of innate immune signaling rather than aggregation-prone MAVS
- Enables both immune suppression and immune activation
- Applicable across a diverse spectrum of diseases
- Includes scalable platform for small-molecule discovery
DEVELOPMENT-TO-DATE: Researchers have identified TOM70 as a critical mediator of MAVS-dependent immune signaling, developed a prototype-protein based TOM70 inhibitor, and established a screening platform for identifying small molecule modulators of TOM70-mediated immune responses.
Related Papers (from the inventors only)
- Li X, Straub J, Medeiros TC, Mehra C, den Brave F, Peker E, Atanassov I, Stillger K, Michaelis JB, Burbridge E, Adrain C, Münch C, Riemer J, Becker T, Pernas LF. Mitochondria shed their outer membrane in response to infection-induced stress. Science. 2022 Jan 14;375(6577):eabi4343. doi: 10.1126/science.abi4343. Epub 2022 Jan 14. PMID: 35025629.
- Mehra, C., Alvarado Valverde, J., Matias, A.M.N. et al. Toxoplasma effector TgROP1 establishes membrane contact sites with the endoplasmic reticulum during infection. Nat Microbiol 10, 3331–3345 (2025). https://doi.org/10.1038/s41564-025-02193-3
Keywords: TOM70, MAVS signaling, innate immunity, mitochondrial signaling, interferon signaling, type I interferon, type II interferon, RIG-I-like receptors, antiviral immunity, autoimmune disease, neuroinflammation, cancer immunotherapy, immune modulation, mitochondrial membrane, vaccine adjuvant