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Adv."],"published-print":{"date-parts":[[2026,7,17]]},"abstract":"<jats:p>Class I histone deacetylases (HDAC1, HDAC2, HDAC3, and HDAC8) are key chromatin regulators, but how they are activated by chaperonin TRiC remains elusive. Using cryo\u2013electron microscopy, cross-linking mass spectrometry, and biochemistry analyses of tagged HDACs overexpressed in HEK293F cells, we identify class I HDACs as TRiC substrates and elucidate the TRiC-assisted folding pathways of HDAC1 and HDAC3 across ATPase cycle, orchestrated by distinct co-chaperone\/cofactor networks. In closed TRiC chamber, both clients adopt near-native conformations and engage similar binding interfaces. In the open state, however, their pathways diverge: HDAC3 involves Hsp70 atop TRiC and PDCD5 within the chamber, whereas HDAC1 involves prefoldin atop TRiC, revealing distinct mechanisms of substrate delivery and folding modulation. 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