Roles of 8-nitro-cGMP in autophagy regulation
© Arimoto 2015
Published: 2 September 2015
A downstream mediator of nitric oxide signaling, 8-nitroguanosine 3?,5?-cyclic monophosphate (8-nitro-cGMP), has been recently identified in various mammalian cell lines [1, 2]. This nitrated version of cGMP modifies Cys residues of proteins (protein S-guanylation) to modulate their functions. In this study, we found that endogenous 8-nitro-cGMP promotes autophagic exclusion of invading group A Streptococci (GAS) from murine macrophages . Interestingly, cytosolic GAS were partly modified by the S-guanylation at their surface, and the S-guanylation level was significantly higher with the autophagosome-encapsulated GAS than the cytosolic counterpart. This finding suggests a possible role of S-guanylation as a tag to recruit bacteria for autophagic degradation. Further analysis revealed that S-guanylation-positive bacteria were selectively modified by Lys63-linked polyubiquitin chains, which is a known molecular determinant for selective transport to autophagosomes via autophagy receptor binding. In accordance with this finding, downregulation of S-guanylation suppressed GAS ubiquitination and retarded the clearance of intracellular GAS.
The results of our study suggested that 8-nitro-cGMP is an endogenous autophagy enhancer that defines targets for sequestration in autophagosomes by recruiting ubiquitin chains.
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