PUMA- and Bax-induced autophagy contributes to apoptosis

Abstract

The p53-inducible BH3-only protein PUMA is a key mediator of p53-dependent apoptosis, and PUMA has been shown to function by activating Bax and mitochondrial outer membrane permeabilization. In this study we describe an ability of PUMA to induce autophagy that leads to the selective removal of mitochondria. This function of PUMA depends on Bax/Bak and can be reproduced by overexpression of Bax. The induction of autophagy coincides with cytochrome c release, and taken together the results suggest that PUMA functions through Bax to induce mitochondrial autophagy in response to mitochondrial perturbations. Surprisingly, inhibition of PUMA or Bax-induced autophagy dampens the apoptotic response, suggesting that under some circumstances the selective targeting of mitochondria for autophagy can enhance apoptosis.

Dimethyl sulfoxide reduces hepatocellular lipid accumulation through autophagy induction

“…At least 30 cells were scored in each of two independent experiments. 32 In addition, HepG2 cells were also co-infected with both GFP-LC3 and RFP-LAMP1 (lysosome associated membrane protein 1-tagged with red fluorescent protein) and then treated with 0.01% DMSO for 16 h. Fluorescence microscopy showed RFP-LAMP1 colocalized with GFP-LC3 in the cytoplasm. For detection of autophagosomes using electron microscopic assay, 0.01% DMSO treated-HepG2 cells were fixed with 2% glutaraldehyde-2% paraformaldehyde buffered with 0.1 M phosphate buffer (pH 7.2) overnight at 4°C, post-fixed with 1% osmium tetroxide in a 0.1M sodium cacodylate buffer (pH 7.4) for 1 h at room temperature, and were dehydrated with a graded series of ethanol.…”

TMBIM6 (transmembrane BAX inhibitor motif containing 6) enhances autophagy and reduces renal dysfunction in a cyclosporine A-induced nephrotoxicity model

“…Although neither overexpression of BAX or BAK1 nor ER-targeted BAK1 has been reported to affect autophagy, 34 BAX has been shown to induce autophagy and autophagic cell death. 35,36 If TMBIM6 affects autophagy through the inhibition of BAX, TMBIM6 might lead to the inhibition of autophagy. Recently, TMBIM6-induced inhibition of autophagy has been reported, 37 but our data indicate that TMBIM6 enhances autophagy, suggesting that enhancement of autophagy is not tightly matched to BAX inhibition.…”

Apoptosis promotes early tumorigenesis

“…PUMA activates Bax/Bak indirectly by relieving the inhibition of anti-apoptotic Bcl-2 family proteins to promote mitochondrial dysfunction and release of the mitochondrial apoptogenic proteins (Figure 1c). Moreover, both PUMA-and Bax-induced autophagy contribute to generating the bioenergetics profile necessary to sustain apoptosis (Yee et al, 2009). PUMA expression is frequently downregulated in melanoma and Burkitt lymphomas.…”