What is it about?
Autophagy is a mechanism through which cells can respond to stress. During autophagy, small portions of the cytoplasm containing superfluous or damaged structures are sequestered and recycled, hence allowing the digestion of macromolecules into their building blocks, which can be used to meed the cell's bioenergetic demands and to rebuild the damaged structures. This rejuvenation mechanism is important for cells to adapt to stress and to survive without causing inflammatory reactions and tissue injury. We have found a protein, ACBP/DBI that is released from cells that become autophagic and then inhibits autophagy in the same cells or other cells. Hence, extracellular ACBP/DBI acts as a checkpoint that inhibits autophagy. Neutralisation of ACBP/DBI with suitable monoclonal antibody hence stimulates autophagy and improves the adaptation of cells to stress.
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Why is it important?
We have shown that targeting ACBP/DBI prevents tissue injury (i.e. cell death, inflammation and fibrosis) in multiple organs (heart, liver and lung) in response to acute or chronic exposure to multiple different toxin, as well as in the context of ischemia. These effects can be obtained with a monoclonal antibody specific for ACBP/DBI. They are mimicked by the removal of the gene coding for ACBP/DBI or mutation of the receptor of ACBP/DBI, demonstrating that the antibody is acting on-target. Since long-term exposure to ACBP/DBI antibodies or genetic ablation of the ACBP/DBI-receptor system has no detectable side effects, it appears that this extracellular autophagy checkpoint can be safely blocked.
Perspectives
In the realm of oncology, so-called immune checkpoint inhibitors (which are monoclonal antibodies targeting CTLA-4, PD-1 or PD-L1) are used to unleash the anticancer immune response and have now been approved for the treatment of dozens of distinct cancer types. By analogy, autophagy checkpoint inhibition can be achieved by monoclonal antibodies targeting ACBP/DBI. Since autophagy plays a broad cytoprotective and anti-inflammatory role across different pathologies including cardiovascular, degenerative and metabolic disorders, it is plausible that its stimulation by autophagy checkpoint inhibition will have a positive impact on several major diseases.
Prof. Guido Kroemer
Read the Original
This page is a summary of: ACBP/DBI protein neutralization confers autophagy-dependent organ protection through inhibition of cell loss, inflammation, and fibrosis, Proceedings of the National Academy of Sciences, October 2022, Proceedings of the National Academy of Sciences,
DOI: 10.1073/pnas.2207344119.
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