Assembly of an Evolutionarily Conserved Alternative Proteasome Isoform in Human Cells

Achuth Padmanabhan; Simone Anh-Thu Vuong; Mark Hochstrasser

doi:10.1016/j.celrep.2016.02.068

Assembly of an Evolutionarily Conserved Alternative Proteasome Isoform in Human Cells

Cell Rep. 2016 Mar 29;14(12):2962-74. doi: 10.1016/j.celrep.2016.02.068. Epub 2016 Mar 22.

Authors

Achuth Padmanabhan¹, Simone Anh-Thu Vuong¹, Mark Hochstrasser²

Affiliations

¹ Department of Molecular Biophysics and Biochemistry, Yale University, 266 Whitney Avenue, New Haven, CT 06520, USA.
² Department of Molecular Biophysics and Biochemistry, Yale University, 266 Whitney Avenue, New Haven, CT 06520, USA. Electronic address: mark.hochstrasser@yale.edu.

Abstract

Targeted intracellular protein degradation in eukaryotes is largely mediated by the proteasome. Here, we report the formation of an alternative proteasome isoform in human cells, previously found only in budding yeast, that 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 an alternative mammalian proteasome isoform and suggest a potential role in enabling cells to adapt to environmental stresses.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

BRCA1 Protein / metabolism
Biological Evolution*
Cadmium Chloride / pharmacology
Cell Line, Tumor
Cell Survival / drug effects
Down-Regulation / drug effects
HEK293 Cells
HeLa Cells
Humans
Immunoblotting
Molecular Chaperones / antagonists & inhibitors
Molecular Chaperones / genetics
Molecular Chaperones / metabolism
Proteasome Endopeptidase Complex / chemistry
Proteasome Endopeptidase Complex / genetics
Proteasome Endopeptidase Complex / metabolism*
Protein Isoforms / genetics
Protein Isoforms / metabolism
Protein Subunits / chemistry
Protein Subunits / genetics
Protein Subunits / metabolism
RNA Interference
RNA, Messenger / metabolism
RNA, Small Interfering / metabolism
Real-Time Polymerase Chain Reaction
Saccharomyces cerevisiae / metabolism
Saccharomyces cerevisiae Proteins / chemistry
Saccharomyces cerevisiae Proteins / genetics
Saccharomyces cerevisiae Proteins / metabolism

Substances

BRCA1 Protein
Molecular Chaperones
Protein Isoforms
Protein Subunits
RNA, Messenger
RNA, Small Interfering
Saccharomyces cerevisiae Proteins
Proteasome Endopeptidase Complex
Cadmium Chloride

Abstract

Publication types

MeSH terms

Substances

Grants and funding