Chediak-Higashi Syndrome: Abnormal Down-Regulation of Protein Kinase C is Responsible for Immunologic Defects

Chediak-Higashi syndrome (CHS) is an autosomal recessive disorder characterized by severe immunologic defects including reduced bacteriocidal activity of neutrophils and impaired natural killer (NK) activity. The diagnostic feature of this syndrome is the presence of giant granules within cells. It was previously demonstrated that the abnormal down-regulation of protein kinase C (PKC) activity in cells from CHS patients and CHS (beige) mice is responsible for the cellular dysfunctions. The rapid down-regulation of PKC activity is found to be associated with the enhancement of calpain-mediated proteolysis of PKC. Moreover, it was reported that the levels in ceramide which is produced by sphingomyelinase (SMase) activation increased in CHS cells and the increased ceramide promotes the proteolysis of PKC. Meanwhile, two independent studies simultaneously identified the homologous genes that are mutated in human CHS and beige mice. The gene, named CHS 1, encodes a protein of 3801 amino acids. CHS 1 is a novel protein and was suggested to be important for lysosomal trafficking. However, the precise role of CHS 1 has not been elucidated. To study the role of CHS 1 protein in the regulation of PKC activity is of great importance to clarify the pathogenesis of CHS.