DNAJC8

DNAJC8 is a nuclear J-domain (Hsp40-family) protein that operates at the intersection of chaperone biology and RNA splicing (PMID:19240134, PMID:38196034). As a cochaperone it directly binds the kinase SRPK1 and bridges it to the Hsp70/Hsp90 system; Hsp90 ATPase inhibition or osmotic shock dissociates this complex, driving SRPK1 nuclear translocation, altered SR protein phosphorylation, and changes in splice site selection (PMID:19240134). Structurally, DNAJC8 is an integral component of the cross-exon pre-A spliceosomal complex, where it stabilizes the assembling prespliceosome together with SF1 and SF3A2 during PRP5-mediated branch site proofreading (PMID:38196034). Beyond splicing, DNAJC8 has chaperone-related activity against aggregation-prone substrates: its C-terminal domain suppresses polyglutamine aggregation in a cellular SCA3/Machado-Joseph model in a J-domain- and Hsp70-independent manner, with a 22-mer C-terminal peptide recapitulating the effect (PMID:27133716). DNAJC8 also influences metabolic signaling, promoting nuclear translocation of PKM2 to upregulate GLUT1 and glucose uptake, an activity blocked by the interactor TIG1 (PMID:29902837).

1. 2009 High

   Established DNAJC8 as a cochaperone that physically couples the SR-protein kinase SRPK1 to the Hsp70/Hsp90 machinery, providing a signal-responsive mechanism linking chaperone status to splicing regulation.

   Evidence Reciprocal Co-IP, direct binding assays, Hsp90 inhibition and osmotic shock, plus SR phosphorylation and splice-site selection readouts in mammalian cells

   PMID:19240134

   Open questions at the time

   • Did not resolve which DNAJC8 domain mediates SRPK1 binding versus Hsp70/Hsp90 engagement
   • Nuclear versus cytoplasmic distribution of DNAJC8 itself during the response not defined
2. 2016 Medium

   Showed that DNAJC8 can suppress protein aggregation through a non-canonical route, mapping the anti-aggregation activity to its C-terminal domain rather than the J-domain/Hsp70 axis.

   Evidence Overexpression and deletion-mutant analysis in SH-SY5Y polyQ cells with co-localization, apoptosis, and oligopeptide suppression assays

   PMID:27133716

   Open questions at the time

   • Biochemical mechanism by which the C-terminal peptide suppresses polyQ aggregation unresolved
   • Single-lab cellular overexpression model; endogenous relevance not established
3. 2018 Medium

   Connected DNAJC8 to metabolic control, demonstrating it promotes PKM2 nuclear translocation and glucose uptake and is negatively regulated by the interactor TIG1.

   Evidence Co-IP, ectopic overexpression, siRNA knockdown, subcellular fractionation, and glucose uptake assays in cervical cancer cells

   PMID:29902837

   Open questions at the time

   • Whether DNAJC8 acts as a direct chaperone for PKM2 or indirectly is unknown
   • Mechanism by which TIG1 binding blocks translocation not defined
   • Single-lab study in one cancer cell context
4. 2024 High

   Placed DNAJC8 structurally within the spliceosome, defining it as a stabilizing component of the cross-exon pre-A complex during branch site proofreading.

   Evidence Atomic cryo-EM structures of human 17S U2 snRNP and the cross-exon pre-A complex

   PMID:38196034

   Open questions at the time

   • Functional consequence of DNAJC8 loss on splicing fidelity not tested
   • Relationship between its spliceosomal role and its SRPK1-cochaperone role unresolved
5. 2025 Medium

   Extended DNAJC8's substrate range to TDP-43, showing it retains TDP-43 in the nucleus and preserves its liquid-phase behavior independently of Hsp70.

   Evidence Hsp70-network screen in yeast and human cells, TDP-43 solubility and live-cell phase assays, and viability assays (preprint)

   PMID:40654997

   Open questions at the time

   • Not yet peer-reviewed
   • Direct binding of DNAJC8 to TDP-43 versus indirect effect not established
   • Domain requirement for TDP-43 retention not mapped

• How DNAJC8's distinct activities — SRPK1 cochaperone, spliceosomal structural subunit, and Hsp70-independent anti-aggregation/phase regulator — are integrated within one protein remains unresolved.
• No structure-function map separating the chaperone and spliceosomal roles
• No knockout phenotype linking the activities in vivo