SAG-dependent UPS regulates macrophage death or survival and immune response

Macrophages, at the frontline of immune defense, undergo apop-tosis as an optimal strategy against a severe microbial infection.However, the mechanism on how the immune cell shifts betweenapoptosis and immune response is under-explored. Here, we showthat ubiquitination by SAG-UPS (sensitive to apoptosis geneubiquitin-proteasome system) confers survival advantage to themacrophages during early infection. We demonstrated that SAGplays a key regulatory role in balancing the ratio of pro- and anti-apoptotic factors in the infected macrophages. SAG-knockdownsignificantly reduced the ubiquitination of Bax and SARM (sterilealpha and HEAT/armadillo-motif-containing protein), stabilizingthese pro-apoptotic factors and leading to intrinsic apoptosis. Incontrast, under chronic infection-inflammation condition, macro-phages overexpress SAG, leading to upregulation of pro-tumori-genic cytokines (IL-1b, IL-6 and TNF-a), and downregulation ofanti-tumorigenic IL-12p40 and anti-inflammatory IL-10. Alto-gether, our findings identified SAG as a survival determinant formacrophages, as well as a modulator in manipulating timelyimmune response. This work provides a novel mechanistic per-spective into how SAG-UPS acts as a functional link betweenimmune defense and apoptosis or immune-overactivation andtumorigenesis. The potency of SAG-UPS suggests it to be a potential target for developing immunomodulatory therapeutics againstautoimmunity, immunodeficiency diseases and cancer.