Sem1 links proteasome stability and specificity to multicellular development

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Abstract
The transition from vegetative growth to multicellular development represents an evolutionary hallmark linked to an oxidative stress signal and controlled protein degradation. We identified the Sem1 proteasome subunit, which connects stress response and cellular differentiation. The sem1 gene encodes the fungal counterpart of the human Sem1 proteasome lid subunit and is essential for fungal cell differentiation and development. A sem1 deletion strain of the filamentous fungus Aspergillus nidulans is able to grow vegetatively and expresses an elevated degree of 20S proteasomes with multiplied ATP-independent catalytic activity compared to wildtype. Oxidative stress induces increased transcription of the genes sem1 and rpn11 for the proteasomal deubiquitinating enzyme. Sem1 is required for stabilization of the Rpn11 deubiquitinating enzyme, incorporation of the ubiquitin receptor Rpn10 into the 19S regulatory particle and efficient 26S proteasome assembly. Sem1 maintains high cellular NADH levels, controls mitochondria integrity during stress and developmental transition. The cellular ubiquitin-proteasome pathway is essential to control cell cycle, gene expression or the response to oxidative stress. Sem1 is conserved in eukaryotes from single cell yeasts to humans as intrinsically disordered and multifunctional protein. Sem1 supports the assembly of several multiprotein complexes but becomes eventually exclusively a subunit of the lid of the 26S proteasome, a cellular machine with a molecular mass of about two megadalton. Defects in the function of the proteasome, which degrades a large fraction of intracellular proteins, result in cancer or neurodegenerative diseases. We showed that Sem1 from a multicellular fungus is required for accurate 26S proteasome assembly and specific activity as prerequisites for mitochondria integrity, oxidative stress response and cell differentiation. Our findings of the complex and dynamic interplay between multiple cellular processes mediated by a small conserved intrinsically unordered protein sheds light and supports current efforts to understand and explore in more details potential therapies to eventually treat age-related human diseases.
Funding Information
  • Cluster of Excellence and DFG Research Center Nanoscale Microscopy and Molecular Physiology of Brain
  • Deutsche Forschungsgemeinschaft (DFG) (SFB860)

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