PLAA (Phospholipase A2 Activating Protein)

Recent discoveries have revealed p97's involvement in pathogen host interactions and circular RNA-mediated regulation, thereby expanding our understanding of its cellular functions. The emerging picture positions p97 as an integrative hub co-ordinating mitochondrial protein homeostasis, organellar dynamics, and cell fate decisions, with therapeutic potential for metabolic and neurodegenerative disorders.

Biochemical approaches, including chemical crosslinking and co-immunoprecipitation, identified key residues critical for Ac/N-degron recognition, while truncation and Split-Ub assays delineated the specific Ac/N-domain necessary for binding. These findings establish a mechanistic framework for Ac/N-degron recognition by MARCHF6, deepening our understanding of Nt-acetylation-mediated proteostasis and its therapeutical implications for diseases linked to dysregulation of Nt-acetylation or MARCHF6, including cancer, birth defects, and metabolic and neurological disorders.

It further addresses how these functions contribute to physiological processes and the development of pathologies, with a particular focus on cancer pathophysiology. Together, it emphasizes non-redundant roles of EndoA proteins in various cellular processes and highlights the complex relationship between membrane trafficking and diseases.

Thus, Synj1, EndoA1, Dnm1, and AAK1 mediate SV recycling and are thus required for sustained synaptic transmission in nociceptive spinal circuits. Disruption of SV recycling effectively reduces nociceptive transmission, providing a novel strategy for pain relief.

In summary, our data identify PLAA as a novel mediator of mitophagy by regulating MCL1-NLRX1 axis. We propose mitophagy as a target for therapeutic intervention in PLAAND.

Additionally, recurrently detected secondary fusion transcripts in patients diagnosed with EWSR1-NFATC2-positive sarcoma were confirmed (COPS4-TBC1D9, PICALM-SYTL2, SMG6-VPS53, and UBE2F-ALS2). In conclusion, this study shows that mRNA capture sequencing enhances the detection rate of pathognomonic fusions and enables the identification of novel and secondary fusion transcripts in sarcomas.

Mechanistically, PLAA inhibited methyltransferase-like 3 (METTL3) expression through the ubiquitin-mediated degradation, and METTL3 stabilized TRPC3 mRNA expression via N6-methyladenosine (mA) modification. Our study verified the function and mechanism of the PLAA-METTL3-TRPC3 axis involved in ovarian cancer metastasis, with a view to providing a potential therapeutic approach for ovarian cancer.