Assembly of an Evolutionarily Conserved Alternative Proteasome Isoform in Human Cells

Abstract

Summary Targeted intracellular protein degradation in eukaryotes is largely mediated by the proteasome. Here we report formation of an alternative proteasome isoform in human cells, previously found only in budding yeast, which bears an altered subunit arrangement in the outer ring of the proteasome core particle. These proteasomes result from incorporation of an additional α4 (PSMA7) subunit in the position normally occupied by α3 (PSMA4). Assembly of ‘α4-α4’ proteasomes depends on the relative cellular levels of α4 and α3, and on the proteasome assembly chaperone PAC3. The oncogenic tyrosine kinases ABL and ARG and the tumor suppressor BRCA1 regulate cellular α4 levels and formation of α4-α4 proteasomes. Cells primed to assemble α4-α4 proteasomes exhibit enhanced resistance to toxic metal ions. Taken together, our results establish the existence of a novel mammalian proteasome isoform and suggest a potential role in enabling cells to adapt to environmental stresses.

Putting it all together: intrinsic and extrinsic mechanisms governing proteasome biogenesis

“…Second, the ability to form α4-α4 proteasomes has been demonstrated recently in mammalian cells, and the levels of these proteasomes correlate inversely with levels of PAC3 in the cell, echoing observations in yeast (Padmanabhan et al 2016). Third, the ability to form α4-α4 proteasomes correlates with resistance to certain heavy metal stresses, a phenotype that is conserved from yeast to humans Padmanabhan et al 2016). Fourth, α4-α4 proteasome levels can be modulated by altered levels of known oncogenes and tumor suppressors, a condition representative of a number of malignancies (Padmanabhan et al 2016).…”

“…This argues that dispensability of α3 is not a quirk of S. cerevisiae genetics. Second, the ability to form α4-α4 proteasomes has been demonstrated recently in mammalian cells, and the levels of these proteasomes correlate inversely with levels of PAC3 in the cell, echoing observations in yeast (Padmanabhan et al 2016). Third, the ability to form α4-α4 proteasomes correlates with resistance to certain heavy metal stresses, a phenotype that is conserved from yeast to humans Padmanabhan et al 2016).…”

“…Third, the ability to form α4-α4 proteasomes correlates with resistance to certain heavy metal stresses, a phenotype that is conserved from yeast to humans Padmanabhan et al 2016). Fourth, α4-α4 proteasome levels can be modulated by altered levels of known oncogenes and tumor suppressors, a condition representative of a number of malignancies (Padmanabhan et al 2016). The conserved ability of α subunits to assemble into canonical and α4-α4 proteasomes, both of which are physiologically relevant, requires two types of α-ring to form.…”

“…One was introduced earlier (see 2.1.2) in the form of alternative α4-α4 proteasomes which are found conserved between yeast and humans Padmanabhan et al 2016;Velichutina et al 2004). It is still not understood how these proteasomes are assembled, or what regulates the process.…”

“…In wild-type yeast, Pba3-Pba4 activity is sufficient to ensure that this is essentially the only type of CP formed. In mammalian cells, PAC3-PAC4 levels may not be sufficient to result solely in canonical CP (Padmanabhan et al 2016).…”