Mrj is a chaperone of the Hsp40 family that regulates Orb2 oligomerization and long-term memory in Drosophila

• Published in: PLoS biology 2024-04, Vol.22 (4), p.e3002585-e3002585
• Main Authors: Desai, Meghal, Hemant, Deo, Ankita, Naik, Jagyanseni, Dhamale, Prathamesh, Kshirsagar, Avinash, Bose, Tania, Majumdar, Amitabha
• Format: Article
• Language: English
• Subjects: Amino acids; Animals; Antibodies; Biology and Life Sciences; Drosophila; Drosophila melanogaster - genetics; Drosophila melanogaster - metabolism; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; Fruit flies; Genes; Genomes; HSP40 Heat-Shock Proteins - genetics; HSP40 Heat-Shock Proteins - metabolism; Hsp40 protein; HSP70 Heat-Shock Proteins - genetics; HSP70 Heat-Shock Proteins - metabolism; Hsp70 protein; Huntingtin; Immunoprecipitation; Insects; Isoforms; Long term memory; Memory, Long-Term - physiology; mRNA Cleavage and Polyadenylation Factors - genetics; mRNA Cleavage and Polyadenylation Factors - metabolism; Mushroom bodies; Mushroom Bodies - metabolism; Mutation; Oligomerization; Oligomers; Physical Sciences; Polyadenylation; Prion protein; Prions; Protein Multimerization; Protein synthesis; Proteins; Research and Analysis Methods; Ribonucleic acid; Ribosomes; RNA; Transcription Factors - genetics; Transcription Factors - metabolism; Yeast
• ISSN: 1545-7885; 1544-9173; 1545-7885
• DOI: 10.1371/journal.pbio.3002585

Orb2 the Drosophila homolog of cytoplasmic polyadenylation element binding (CPEB) protein forms prion-like oligomers. These oligomers consist of Orb2A and Orb2B isoforms and their formation is dependent on the oligomerization of the Orb2A isoform. Drosophila with a mutation diminishing Orb2A's prion-like oligomerization forms long-term memory but fails to maintain it over time. Since this prion-like oligomerization of Orb2A plays a crucial role in the maintenance of memory, here, we aim to find what regulates this oligomerization. In an immunoprecipitation-based screen, we identify interactors of Orb2A in the Hsp40 and Hsp70 families of proteins. Among these, we find an Hsp40 family protein Mrj as a regulator of the conversion of Orb2A to its prion-like form. Mrj interacts with Hsp70 proteins and acts as a chaperone by interfering with the aggregation of pathogenic Huntingtin. Unlike its mammalian homolog, we find Drosophila Mrj is neither an essential gene nor causes any gross neurodevelopmental defect. We observe a loss of Mrj results in a reduction in Orb2 oligomers. Further, Mrj knockout exhibits a deficit in long-term memory and our observations suggest Mrj is needed in mushroom body neurons for the regulation of long-term memory. Our work implicates a chaperone Mrj in mechanisms of memory regulation through controlling the oligomerization of Orb2A and its association with the translating ribosomes.