Highlights d Parabacteroides distasonis alleviates obesity and obesityrelated dysfunctions in mice. d P. distasonis generates succinate and secondary bile acids in the gut. d P. distasonis activates intestinal gluconeogenesis (IGN) and FXR pathways in the gut. d Succinate is a ligand of fructose-1,6-bisphosphatase, the rate-limiting enzyme in IGN.

No abstract

Autophagy is an intracellular degradation system that delivers cytoplasmic constituents to the lysosome, and loss of autophagy has been linked to increased genome instability. Here, we report that loss of autophagy is coupled to reduced histone H2A ubiquitination after DNA damage. p62/SQSTM1, which accumulates in autophagy-defective cells, directly binds to and inhibits nuclear RNF168, an E3 ligase essential for histone H2A ubiquitination and DNA damage responses. As a result, DNA repair proteins such as BRCA1, RAP80, and Rad51 cannot be recruited to the sites of DNA double-strand breaks (DSBs), which impairs DSB repair. Moreover, nuclear-localized p62 increased the sensitivity of tumor cells to radiation both in vitro and in vivo, and this required its interaction with RNF168. Our findings indicate that autophagy-deficiency-induced p62 accumulation results in inhibition of histone ubiquitination and highlight the complex relationship between autophagy and the DNA damage response.

Abbreviations: ATG, autophagy related; FOXO1, forkhead box O1; FOXO3, forkhead box O3; GFP, green fluorescent protein; MAP1LC3, microtubule-associated protein 1 light chain 3; PIK3CA, class I PI3K catalytic subunit the BECN1-PtdIns3K complex to promote autophagosome formation. 16,17 Recent evidence has revealed that the FOXO protein family members FOXO1 and FOXO3 promote autophagy. [18][19][20][21][22][23] In skeletal muscle cells, FOXO3 directly upregulates autophagy-related genes, such as microtubule-associated protein 1 light chain 3 (MAP1LC3) and BCL2/adenovirus E1B 19-kDa interacting protein 3 (BNIP3).19 FOXO1 has both transcription-dependent and transcription-independent roles in autophagy. In mouse cardiomyocytes, FOXO1 is deacetylated by the NAD-dependent deacetylase sirtuin-1 (SIRT1) that, in turn, induces the expression of the RAS-related GTP-binding protein RAB7A, which mediates the fusion of mature autophagic vesicles with lysosomes. 21 In addition, FOXO1 mediates starvation-induced autophagy through a transcription-independent mechanism in human cancer cells. We have previously observed that cytoplasmic FOXO1 is required for serum starvation-or H 2 O 2 -induced autophagy in cancer cells. Under these conditions, FOXO1 became acetylated and dissociated from SIRT2 in the cytoplasm, and the acetylated FOXO1, in turn, binds to ATG7 to promote autophagy. 23 Therefore, it is ©2012 Landes Bioscience. Do not distribute.www.landesbioscience.com Autophagy