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Publication : Ubiquitination by SAG regulates macrophage survival/death and immune response during infection.

First Author  Chang SC Year  2014
Journal  Cell Death Differ Volume  21
Issue  9 Pages  1388-98
PubMed ID  24786833 Mgi Jnum  J:258842
Mgi Id  MGI:6141348 Doi  10.1038/cdd.2014.54
Citation  Chang SC, et al. (2014) Ubiquitination by SAG regulates macrophage survival/death and immune response during infection. Cell Death Differ 21(9):1388-98
abstractText  The checkpoint between the life and death of macrophages is crucial for the host''s frontline immune defense during acute phase infection. However, the mechanism as to how the immune cell equilibrates between apoptosis and immune response is unclear. Using in vitro and ex vivo approaches, we showed that macrophage survival is synchronized by SAG (sensitive to apoptosis gene), which is a key member of the ubiquitin-proteasome system (UPS). When challenged by pathogen-associated molecular patterns (PAMPs), we observed a reciprocal expression profile of pro- and antiapoptotic factors in macrophages. However, SAG knockdown disrupted this balance. Further analysis revealed that ubiquitination of Bax and SARM (sterile alpha- and HEAT/armadillo-motif-containing protein) by SAG-UPS confers survival advantage to infected macrophages. SAG knockdown caused the accumulation of proapoptotic Bax and SARM, imbalance of Bcl-2/Bax in the mitochondria, induction of cytosolic cytochrome c and activation of caspase-9 and -3, all of which led to disequilibrium between life and death of macrophages. In contrast, SAG-overexpressing macrophages challenged with PAMPs exhibited upregulation of protumorigenic cytokines (IL-1beta, IL-6 and TNF-alpha), and downregulation of antitumorigenic cytokine (IL-12p40) and anti-inflammatory cytokine (IL-10). This suggests that SAG-dependent UPS is a key switch between immune defense and apoptosis or immune overactivation and tumorigenesis. Altogether, our results indicate that SAG-UPS facilitates a timely and appropriate level of immune response, prompting future development of potential immunomodulators of SAG-UPS.
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