Coiled-coil homo-oligomerization and disaggregase Hsp104 act in parallel to stabilize orphan septins.

Multiple septin family proteins co-assemble with strict subunit stoichiometry into hetero-oligomers. In the absence of native septin partners, purified septins aggregate in vitro, and "orphan" septins are found in pathological aggregates associated with neurodegenerative diseases. Cytosolic chaperones bind the septin GTPase domain to promote on-pathway septin folding but it was unclear how cells manage orphan septins to maintain septin subunit stoichiometry. Most septins have C-terminal domains (CTDs) that form heteromeric coiled coils within or between septin complexes. Here we present evidence that orphan yeast septins are protected from proteasomal degradation by forming transient coiled-coil homodimers and trimers and, in parallel, by the disaggregase chaperone Hsp104. Septins unable to undergo CTD-mediated homo-oligomerization require Hsp104 to accumulate to super-stoichiometric levels. We show that the number of septin-encoding mRNAs per yeast cell is low and variable, creating opportunities for transient subunit imbalances. These findings reveal a novel role for coiled coils and the cellular proteostasis machinery in the fidelity of higher-order septin assembly.