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IRF8 directs stress-induced autophagy in macrophages and promotes clearance of Listeria monocytogenes.

Gupta M, Shin DM, Ramakrishna L, Goussetis DJ, Platanias LC, Xiong H, Morse HC, Ozato K - Nat Commun (2015)

Bottom Line: Autophagy, activated by many stresses, plays a critical role in innate immune responses.Here we show that interferon regulatory factor 8 (IRF8) is required for the expression of autophagy-related genes in dendritic cells.IRF8 directly activates many genes involved in various steps of autophagy, promoting autophagosome formation and lysosomal fusion.

View Article: PubMed Central - PubMed

Affiliation: Program in Genomics of Differentiation, NICHD, National Institutes of Health, Bethesda, Maryland 20892, USA.

ABSTRACT
Autophagy, activated by many stresses, plays a critical role in innate immune responses. Here we show that interferon regulatory factor 8 (IRF8) is required for the expression of autophagy-related genes in dendritic cells. Furthermore in macrophages, IRF8 is induced by multiple autophagy-inducing stresses, including IFNγ and Toll-like receptor stimulation, bacterial infection, starvation and by macrophage colony-stimulating factor. IRF8 directly activates many genes involved in various steps of autophagy, promoting autophagosome formation and lysosomal fusion. Consequently, Irf8(-/-) macrophages are deficient in autophagic activity, and excessively accumulate SQSTM1 and ubiquitin-bound proteins. We show that clearance of Listeria monocytogenes in macrophages requires IRF8-dependent activation of autophagy genes and subsequent autophagic capturing and degradation of Listeria antigens. These processes are defective in Irf8(-/-) macrophages where uninhibited bacterial growth ensues. Together these data suggest that IRF8 is a major autophagy regulator in macrophages, essential for macrophage maturation, survival and innate immune responses.

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A model for IRF8 dependent autophagy in MΦsUpon various stresses (IFNγ/TLR stimulation, Listeria infection, starvation and M-CSF stimulation), IRF8 is activated and promotes the expression of a series of autophagy genes. These genes encode factors active at various stages of autophagy, largely covering the whole autophagic cascade. Irf8-/- MΦs are defective in autophagic activation and fail to degrade target ubiquitin conjugated factors, organelle and intracellular pathogens. Together, IRF8 acts as an autophagy master regulator in MΦs to coordinate stress responses critical for innate immunity.
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Figure 8: A model for IRF8 dependent autophagy in MΦsUpon various stresses (IFNγ/TLR stimulation, Listeria infection, starvation and M-CSF stimulation), IRF8 is activated and promotes the expression of a series of autophagy genes. These genes encode factors active at various stages of autophagy, largely covering the whole autophagic cascade. Irf8-/- MΦs are defective in autophagic activation and fail to degrade target ubiquitin conjugated factors, organelle and intracellular pathogens. Together, IRF8 acts as an autophagy master regulator in MΦs to coordinate stress responses critical for innate immunity.


IRF8 directs stress-induced autophagy in macrophages and promotes clearance of Listeria monocytogenes.

Gupta M, Shin DM, Ramakrishna L, Goussetis DJ, Platanias LC, Xiong H, Morse HC, Ozato K - Nat Commun (2015)

A model for IRF8 dependent autophagy in MΦsUpon various stresses (IFNγ/TLR stimulation, Listeria infection, starvation and M-CSF stimulation), IRF8 is activated and promotes the expression of a series of autophagy genes. These genes encode factors active at various stages of autophagy, largely covering the whole autophagic cascade. Irf8-/- MΦs are defective in autophagic activation and fail to degrade target ubiquitin conjugated factors, organelle and intracellular pathogens. Together, IRF8 acts as an autophagy master regulator in MΦs to coordinate stress responses critical for innate immunity.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4363081&req=5

Figure 8: A model for IRF8 dependent autophagy in MΦsUpon various stresses (IFNγ/TLR stimulation, Listeria infection, starvation and M-CSF stimulation), IRF8 is activated and promotes the expression of a series of autophagy genes. These genes encode factors active at various stages of autophagy, largely covering the whole autophagic cascade. Irf8-/- MΦs are defective in autophagic activation and fail to degrade target ubiquitin conjugated factors, organelle and intracellular pathogens. Together, IRF8 acts as an autophagy master regulator in MΦs to coordinate stress responses critical for innate immunity.
Bottom Line: Autophagy, activated by many stresses, plays a critical role in innate immune responses.Here we show that interferon regulatory factor 8 (IRF8) is required for the expression of autophagy-related genes in dendritic cells.IRF8 directly activates many genes involved in various steps of autophagy, promoting autophagosome formation and lysosomal fusion.

View Article: PubMed Central - PubMed

Affiliation: Program in Genomics of Differentiation, NICHD, National Institutes of Health, Bethesda, Maryland 20892, USA.

ABSTRACT
Autophagy, activated by many stresses, plays a critical role in innate immune responses. Here we show that interferon regulatory factor 8 (IRF8) is required for the expression of autophagy-related genes in dendritic cells. Furthermore in macrophages, IRF8 is induced by multiple autophagy-inducing stresses, including IFNγ and Toll-like receptor stimulation, bacterial infection, starvation and by macrophage colony-stimulating factor. IRF8 directly activates many genes involved in various steps of autophagy, promoting autophagosome formation and lysosomal fusion. Consequently, Irf8(-/-) macrophages are deficient in autophagic activity, and excessively accumulate SQSTM1 and ubiquitin-bound proteins. We show that clearance of Listeria monocytogenes in macrophages requires IRF8-dependent activation of autophagy genes and subsequent autophagic capturing and degradation of Listeria antigens. These processes are defective in Irf8(-/-) macrophages where uninhibited bacterial growth ensues. Together these data suggest that IRF8 is a major autophagy regulator in macrophages, essential for macrophage maturation, survival and innate immune responses.

Show MeSH
Related in: MedlinePlus