Molecular Functions of NPHP8 and Associated Diseases: Advances and Challenges
WANG Suhui1, XU Chuang1, JIANG Lin1, LI Ya1, MA Zhao1, ZHANG Yixin1, HUI Zi1, MENG Dan2*, WANG Liang1*
The NPHP (nephronophthisis) gene family was originally identified in the pathogenic genes of nephronophthisis and is evolutionarily conserved in humans and major ciliary model organisms. To date, dozens of genes in this family, among which NPHP1, NPHP3, NPHP4, and NPHP8 are best characterized, have been described. These proteins mainly locate at the ciliary TZ (transition zone), where they assemble into a core “gate”module that selectively controls protein trafficking in and out of the cilium. NPHP8 (nephronophthisis-8), a core member of this family, directly orchestrates the assembly and architectural maintenance of the TZ complex, thereby preserving the molecular and structural integrity of the cilium. Beyond its structural role, NPHP8 modulates ciliumdependent signaling by regulating both Hh (hedgehog) pathway activity and proteasomal function, consequently influencing cell proliferation and differentiation. Mutations in NPHP8 underlie a spectrum of ciliopathies, whereas its abnormal expression is associated with the progression of multiple cancers, indicating that NPHP8 may serve as a therapeutic target. Here, this paper provides a comprehensive review of the molecular functions of NPHP8 and its involvement in human disease, with the aim of guiding precision prevention and treatment of NPHP8-related ciliopathies and malignancies.
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