3.5. PA28γ: Impact on autophagy and metabolism

Highly selective proteolytic systems such as UPS or UIPP, responsible for the selective and regulated degradation of proteins, are supplemented by autophagosomes and ub-based substrate labeling for cargo selection. Ubiquitin-like proteins and a corresponding conjugation system are initially involved in phagophore formation, a process, which integrates phosphatidylethanolamine-linked LC3-II into both leaflets of the autophagosome. Cargo receptors for ubiquitinated proteins such as p62 are recruited to autophagosomes via LIR domains (LC3 interacting region (LIR)). Finally, degradation of bulky aggregates or organelles can be conducted by lysosomal proteases during basal autophagy. Under environmental stress conditions, as an adaptive survival strategy, autophagy can be gradually upregulated, avoiding excessive activity of autophagy which may lead to cell death. The regulation of this sophisticated machinery for bulk degradation has recently been reviewed [81]. Interestingly, since Bcl-2 family proteins are closely linked to cytoprotective responses, regulation of metabolism, and apoptosis, the involvement into regulation of autophagy is not surprising. Generally, anti-apoptotic members such as BclXL can inhibit autophagy, whereas pro-apoptotic BH3-only proteins may induce autophagy. The principal behind anti-apoptotic or anti-autophagic roles of BclXL may be considered simply the same, while complexity in cross talk between autophagy and apoptosis majorly results from BclXL phosphorylation and subcellular localization. BclXL has been reported to be localized in the cytosol, the nuclear envelope, the endoplasmic reticulum, and the outer mitochondrial membrane, establishing BclXL pools of different functionalities. In anti-apoptotic signaling, BclXL antagonizes pro-apoptotic proteins via physically interacting with Bax, cytochrome c, or cytosolic p53, preventing MOMP [82, 83]. Binding of Beclin 1 to BclXL prevents assembly and activation of class III phosphatidylinositol 3-kinase (PI3K) complex, which is involved in autophagosome function.

Similarly, multifaceted as pro-survival factor BclXL [82], anti-apoptotic PA28γ protein reveals a plethora of PPIs and functional versatility. Targeting of deacetylase SirT1 for PA28γ-20S proteasome-mediated UIPP degradation was shown to regulate liver autophagy [84]. Deficiency of PA28γ as well as energy starvation dissociates the REGγ-SirT1 interaction and releases SirT1 to deacetylate components of the autophagy machinery, thereby stimulating autophagy.

Analyzing metabolic parameter of PA28γ knockout mice, a reduction of ATP consumption, possibly due to an inhibition of rDNA transcription, has been demonstrated. Under starvation, nucleolar deacetylase SirT7 was negatively regulated by PA28γ. Consistently, depletion of PA28γ induced increased Sirt7 levels, as well as increased ATP consumption. These observations might be of relevance for cancer therapy, since PA28γ depletion sensitizes tumors to treatment with hexokinase inhibitor 2-desoxy-glucose [85].
