Preserve or destroy: Orphan protein proteostasis and the heat shock response

Most eukaryotic genes encode polypeptides that are either obligate members of hetero-stoichiometric complexes or clients of organelle-targeting pathways. Proteins in these classes can be released from the ribosome as "orphans"—newly synthesized proteins not associated with their stoichiometric binding partner(s) and/or not targeted to their destination organelle. Here we integrate recent findings suggesting that although cells selectively degrade orphan proteins under homeostatic conditions, they can preserve them in chaperone-regulated biomolecular condensates during stress. These orphan protein condensates activate the heat shock response (HSR) and represent subcellular sites where the chaperones induced by the HSR execute their functions. Reversible condensation of orphan proteins may broadly safeguard labile precursors during stress.