Dnajb12, an endoplasmic reticulum (ER) transmembrane Hsp40 chaperone, plays a crucial role in protein quality control. It cooperates with cytosolic Hsp70 on the ER's cytoplasmic face, facilitating the triage of nascent polytopic membrane proteins for folding or degradation, and is involved in ER-associated degradation (ERAD) and ER-associated autophagy (ERAA) pathways [1,2]. It also contributes to maintaining the normal physiological state of organisms under stress conditions in insects [4].

In the context of misfolded membrane proteins, DNAJB12-Hsp70 complexes maintain degradation intermediates in a detergent-soluble and degradation-competent state. For example, in the case of N1303K-CFTR, a misfolded form of the ion channel CFTR, DNAJB12-Hsp70 triage its arrested intermediates for ER-associated autophagy. Depletion of JB12 prevents N1303K-CFTR from entering the membranes of ER-connected phagophores and trafficking to autolysosomes [1]. In a plant reovirus (Southern rice black-streaked dwarf virus, SRBSDV), the virus hijacks the DNAJB12-Hsc70 chaperone complex to promote the ER-to-cytosol export of P7-1 tubules for proper assembly, enabling viral spread in its planthopper vector. Knockdown of DNAJB12 strongly inhibits P7-1 tubule assembly in vivo and suppresses effective viral spread [3].

In conclusion, Dnajb12 is essential for the triage of misfolded membrane proteins in the ER, determining their fate of folding, proteasomal degradation, or lysosomal degradation via autophagy. Its study through loss-of-function experiments, such as knockdown in relevant models, reveals its significance in processes related to protein misfolding-associated diseases and viral spread [1,3].