Multifaceted Roles of Guanylate-Binding Proteins in Cancer

Abstract

Guanylate-binding proteins (GBPs), encompassing GBP1 through GBP7 in humans, are interferon-inducible large GTPases of the dynamin superfamily, renowned for their pivotal roles in cell-autonomous immunity against intracellular pathogens such as viruses, bacteria, and protozoa. By recognizing pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), GBPs orchestrate lysosomal targeting, regulate inflammatory cascades, and modulate apoptosis to protect host tissues from immune-mediated damage. Beyond their foundational roles in immunity, GBPs exhibit context-dependent effects in human cancer, promoting malignancy in some tumors through enhanced immune signaling, inhibition of apoptosis, and resistance to therapies, or suppressing tumor growth through immune activation and cell cycle regulation. This comprehensive review explores the structural intricacies, immune functions, and multifaceted contributions of human GBPs to cancer, delving into their molecular mechanisms, prognostic potential, and therapeutic implications. We incorporate the latest insights to highlight how understanding GBP regulation could reshape cancer treatment strategies.

Keywords: GTPase; cancer; guanylate-binding proteins; immunity.

Figure 1

Genomic organization and structure of guanylate-binding proteins (GBPs). (A) Chromosomal organization of genes encoding human GBPs (hGBPs) on chromosome 1q22.2. (B) hGBP1 comprises an N-terminal large GTPase (LG) domain, a middle domain (MD), and a C-terminal GTPase effector domain (GED). In addition, hGBP1 contains a conserved CaaX motif essential for post-translational modification. Two positively charged stretches (⁶¹KKK⁶³ and ⁵⁸⁴RRR⁵⁸⁶) facilitate electrostatic interactions with bacterial lipopolysaccharide (LPS). (C) Crystal structure of hGBP1 (PDB:1DG3). Note: This figure is adapted from Ref. [4].