Clpb-KO Mouse

ClpB, a member of class 1 AAA+ proteins, is a key chaperone belonging to the Hsp100/Clp subfamily of the AAA+ ATPases [1,4,8]. It functions as an ATP-dependent disaggregase, rescuing aggregated cellular proteins, often in cooperation with the DnaK chaperone system [4,7,8]. This disaggregation activity is crucial for bacterial survival under various stress conditions, such as heat shock, osmolarity changes, oxidative stress, and during infection or inflammation [1,4,5,8]. In plants, ClpB proteins are also involved in heat stress tolerance [5].

In bacteria, ClpB-null environments show a stress-specific aggregation phenotype, and ClpB preferentially attaches to mitochondrial RNA granules and translation initiation components [2,3]. In pathogenic bacteria, ClpB supports virulence, for example in Leptospira interrogans, although its specific function in leptospiral virulence is yet to be fully elucidated [8]. In humans, CLPB mutations are associated with 3-methylglutaconic aciduria and neutropenia, and CLPB deficiency may lead to a mitochondrial chaperonopathy with neutropenia and neurological presentation [2,6].

In conclusion, ClpB is essential for maintaining protein homeostasis under stress in bacteria, plants, and potentially in human mitochondria. The study of ClpB knockout models, especially in bacteria, has revealed its role in stress responses and bacterial virulence. In humans, understanding ClpB function through such models may provide insights into diseases associated with its mutations, like 3-methylglutaconic aciduria, neutropenia, and mitochondrial chaperonopathies [1-3,5-8].

References:

1. Alam, Athar, Bröms, Jeanette E, Kumar, Rajender, Sjöstedt, Anders. 2021. The Role of ClpB in Bacterial Stress Responses and Virulence. In Frontiers in molecular biosciences, 8, 668910. doi:10.3389/fmolb.2021.668910. https://pubmed.ncbi.nlm.nih.gov/33968993/

2. Baker, Megan J, Blau, Kai Uwe, Anderson, Alexander J, Langer, Thomas, Stojanovski, Diana. 2024. CLPB disaggregase dysfunction impacts the functional integrity of the proteolytic SPY complex. In The Journal of cell biology, 223, . doi:10.1083/jcb.202305087. https://pubmed.ncbi.nlm.nih.gov/38270563/

3. Auburger, Georg, Key, Jana, Gispert, Suzana. 2022. The Bacterial ClpXP-ClpB Family Is Enriched with RNA-Binding Protein Complexes. In Cells, 11, . doi:10.3390/cells11152370. https://pubmed.ncbi.nlm.nih.gov/35954215/

4. Kędzierska-Mieszkowska, Sabina, Zolkiewski, Michal. 2021. Hsp100 Molecular Chaperone ClpB and Its Role in Virulence of Bacterial Pathogens. In International journal of molecular sciences, 22, . doi:10.3390/ijms22105319. https://pubmed.ncbi.nlm.nih.gov/34070174/

5. Mishra, Ratnesh Chandra, Grover, Anil. 2015. ClpB/Hsp100 proteins and heat stress tolerance in plants. In Critical reviews in biotechnology, 36, 862-74. doi:10.3109/07388551.2015.1051942. https://pubmed.ncbi.nlm.nih.gov/26121931/

6. Mróz, D, Jagłowska, J, Wevers, R A, Ziętkiewicz, S. . CLPB Deficiency, a Mitochondrial Chaperonopathy With Neutropenia and Neurological Presentation. In Journal of inherited metabolic disease, 48, e70025. doi:10.1002/jimd.70025. https://pubmed.ncbi.nlm.nih.gov/40194906/

7. Lee, Sukyeong, Sowa, Mathew E, Choi, Jae-Mun, Tsai, Francis T F. . The ClpB/Hsp104 molecular chaperone-a protein disaggregating machine. In Journal of structural biology, 146, 99-105. doi:. https://pubmed.ncbi.nlm.nih.gov/15037241/

8. Kędzierska-Mieszkowska, Sabina, Arent, Zbigniew. 2020. AAA+ Molecular Chaperone ClpB in Leptospira interrogans: Its Role and Significance in Leptospiral Virulence and Pathogenesis of Leptospirosis. In International journal of molecular sciences, 21, . doi:10.3390/ijms21186645. https://pubmed.ncbi.nlm.nih.gov/32932775/