Dnajb12-KO Mouse

Dnajb12, an endoplasmic reticulum (ER)-transmembrane Hsp40 chaperone, is crucial for 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 pathways like ER-associated degradation (ERAD) and ER-associated autophagy (ERAA) [1,2]. It also has roles in maintaining ER-calcium homeostasis and is related to the ER-membrane penetration of viral particles [2,3]. Genetic models can be valuable to further explore its functions.

In misfolded membrane protein handling, DNAJB12-Hsp70 complexes maintain degradation intermediates in a soluble state. For example, N1303K-CFTR intermediates, which are clients of these complexes, have a relatively long half-life. DNAJB12 depletion prevents N1303K-CFTR from entering autophagy-related membranes [1]. In the case of a plant reovirus, the DNAJB12-Hsc70 chaperone complex is hijacked to promote viral spread by facilitating ER-to-cytosol export of a viral protein [4]. Also, knockdown of DNAJB12 in ER-stressed cells impairs the amount of an ER redox-chaperone in the cytosolic fraction [3].

In conclusion, Dnajb12 is essential for the triage of misfolded membrane proteins in the ER, playing a key role in their folding, proteasomal degradation, or autophagic disposal. Studies, including those using gene knockdown (akin to loss-of-function models), have revealed its significance in processes related to protein quality control, viral spread, and ER stress responses, which may have implications for understanding and treating diseases associated with protein misfolding and viral infections.

References:

1. He, Lihua, Kennedy, Andrew S, Houck, Scott, Ren, Hong Yu, Cyr, Douglas M. 2021. DNAJB12 and Hsp70 triage arrested intermediates of N1303K-CFTR for endoplasmic reticulum-associated autophagy. In Molecular biology of the cell, 32, 538-553. doi:10.1091/mbc.E20-11-0688. https://pubmed.ncbi.nlm.nih.gov/33534640/

2. Kennedy, Andrew, Cyr, Douglas M. 2022. DNAJB12 and Hsp70 Mediate Triage of Misfolded Membrane Proteins for Proteasomal versus Lysosomal Degradation. In Autophagy reports, 1, 559-562. doi:10.1080/27694127.2022.2139335. https://pubmed.ncbi.nlm.nih.gov/36743458/

3. Purificação, Aline Dias da, Debbas, Victor, Tanaka, Leonardo Yuji, Laurindo, Francisco Rafael Martins, Oliveira, Percillia Victoria Santos. 2023. DNAJB12 and DNJB14 are non-redundant Hsp40 redox chaperones involved in endoplasmic reticulum protein reflux. In Biochimica et biophysica acta. General subjects, 1868, 130502. doi:10.1016/j.bbagen.2023.130502. https://pubmed.ncbi.nlm.nih.gov/37925033/

4. Liang, Qifu, Wan, Jiajia, Liu, Huan, Chen, Hongyan, Wei, Taiyun. 2021. A plant reovirus hijacks the DNAJB12-Hsc70 chaperone complex to promote viral spread in its planthopper vector. In Molecular plant pathology, 23, 805-818. doi:10.1111/mpp.13152. https://pubmed.ncbi.nlm.nih.gov/34668642/