The many faces of the autophagy machinery: LAP as a critical regulator of inflammation
Genome-wide association studies (GWAS) have consistently highlighted autophagy machinery genes as risk loci for systemic lupus erythematosus (SLE), an autoimmune disease characterized by the recognition of, and reaction against, self-antigens. However to date, how the autophagy machinery functions in preventing SLE and other autoimmune pathologies has remained undetermined.
IRP researchers, led by Jennifer Martinez, Ph.D., discovered that LC3-associated phagocytosis (LAP), not canonical autophagy, was required to prevent the development of SLE in mice. They demonstrated that LAP exerts this protective effect by facilitating the efficient clearance of dying cells, preventing the production of inflammatory cytokines and the subsequent development of SLE symptoms.
The characterization of LAP as a critical regulator of inflammation in response to dying cells provides us with a greater understanding of the mechanisms underpinning the autoimmune reaction that is characteristic of SLE. In addition to gaining a greater understanding of how the disease develops, this discovery may lead to the development of anti-inflammatory therapeutics that specifically target LAP, while leaving the quality control mechanisms of canonical autophagy unaffected. Looking to the future, further GWAS analysis could lead to the identification of other autoimmune and autoinflammatory pathologies that are associated with LAP deficiencies.
Martinez J, Cunha LD, Park S, Yang M, Lu Q, Orchard R, Li QZ, Yan M, Janke L, Guy C, Linkermann A, Virgin HW, Green DR. (2016). Noncanonical autophagy inhibits the autoinflammatory, lupus-like response to dying cells. Nature. 533(7601):115-119.