Removal of damaged proteins during ES cell fate specification requires the proteasome activator PA28

Abstract

In embryonic stem cells, removal of oxidatively damaged proteins is triggered upon the first signs of cell fate specification but the underlying mechanism is not known. Here, we report that this phase of differentiation encompasses an unexpected induction of genes encoding the proteasome activator PA28αβ (11S), subunits of the immunoproteasome (20Si), and the 20Si regulator TNFα. This induction is accompanied by assembly of mature PA28-20S(i) proteasomes and elevated proteasome activity. Inhibiting accumulation of PA28α using miRNA counteracted the removal of damaged proteins demonstrating that PA28αβ has a hitherto unidentified role required for resetting the levels of protein damage at the transition from self-renewal to cell differentiation.

PA28 modulates antigen processing and viral replication during coxsackievirus B3 infection

“…The Wang laboratory provided data for an anti-oxidative function of the PA28 complex specifically in cardiomyocytes, all being in line with previous reports by other groups on PA28-20S proteasome complex-dependent proteolysis irrespective of ubiquitin/ubiquitination [25]. PA28 is important for cell fate determination in embryonic stem cells [26] and was connected to reduced obesity-induced ER-stress and insulin resistance in the liver [27]. …”

Protein Quality Control and Metabolism: Bidirectional Control in the Heart

“…In contrast, over-expression of the PA28α (an alternative regulatory subunit independent of ubiquitin chain targeting) in cardiomyocytes to enhance proteasomal protease activity protects mouse hearts from I/R damage and prevents accumulation of misfolded proteins (Li et al, 2011). This finding may be elucidated by a recent report that PA28α can play a special role in the removal of oxidatively damaged proteins (Hernebring et al, 2013). Thus, modulation of the UPS within cardiomyocytes versus non-cardiomyocytes results in distinct phenotypes, calling for caution when addressing the function of UPS in cardiac I/R injury.…”

The role of protein clearance mechanisms in organismal ageing and age-related diseases

“…Since the passage of damaged proteins to daughter cells could compromise the ageing process of an organism, increased proteasome activity could be required to generate a cell lineage with an intact proteome. Notably, the degradation of damaged proteins is triggered on the first signs of mESC differentiation via induction of PA28ab 69,70 . Furthermore, both ESCs exhibit higher autophagy activity on early differentiation 71 .…”