Pld4-KO Mouse

Pld4, or Phospholipase D4, is an enzyme involved in multiple biological processes. It is an endolysosomal exonuclease of ssDNA and ssRNA, regulating innate immunity [3,4,6,7]. It also participates in the synthesis of lysosomal S,S-Bis(monoacylglycero)phosphate (S,S-BMP), a crucial phospholipid for lipid degradation in lysosomes, especially for gangliosides [1,2].

Deletion of Pld4 in murine tissues (spleen) significantly reduced S,S-BMP levels, leading to gangliosidosis and lysosomal abnormalities [1,2]. Pld4 -/- mice accumulate small ssRNAs and develop spontaneous fatal hemophagocytic lymphohistiocytosis (HLH) characterized by inflammatory liver damage and overproduction of Interferon (IFN)-γ, suggesting its role in regulating nucleic acid sensing pathways [3]. In addition, Pld4 mutant mice showed autoimmune phenotypes similar to systemic lupus erythematosus (SLE), including splenomegaly, lymphadenopathy, and autoantibody production, indicating its involvement in SLE-related processes [5].

In conclusion, Pld4 is essential for lipid degradation in lysosomes and regulation of innate immunity. The gene knockout mouse models have revealed its role in diseases such as gangliosidosis, HLH, and SLE, highlighting its importance in understanding the pathogenesis of these diseases and potentially guiding the development of new therapeutic strategies.