Pggt1b, the geranylgeranyl transferase type-1 subunit beta, is a key enzyme in the mevalonate metabolism-fueled protein prenylation pathway. Protein prenylation, especially geranylgeranylation mediated by Pggt1b, is involved in multiple cellular signaling processes, such as regulating the function of small G-proteins like RhoA, Rac1, and Cdc42, which are crucial for cell migration, cytoskeleton dynamics, and immune cell function [1,2,3,4].

In Pggt1bΔCD4 mice (T-cell-specific disruption of Pggt1b), they developed spontaneous colitis, with increased T-cell localization to the intestine due to higher integrin alpha4beta7 expression on CD4+ T cells, and elevated levels of inflammatory cytokines. This shows that loss of Pggt1b from T cells impairs RhoA function, leading to colitis development [1]. Treg cell-specific deletion of Pggt1b in mice caused fatal autoimmunity, associated with reduced effector Treg (eTreg) cell accumulation. Pggt1b acts as a regulator of TCR-dependent transcriptional programming and Rac-mediated signaling for eTreg cell differentiation and immune tolerance [2]. Epithelial Pggt1b deletion in mice (Pggt1b iΔIEC) led to cytoskeleton rearrangement, cell overcrowding, epithelial leakage, and mucosal inflammation, identifying RAC1 as a GGTase target involved in these processes [3]. Myeloid cell-specific Pggt1b knockout mice showed that Pggt1b positively regulates pro-inflammatory responses in resiquimod-stimulated bone marrow-derived macrophages via the NF-κB signaling pathway [4].

In conclusion, Pggt1b is essential for normal immune cell function, immune tolerance, and maintaining epithelial integrity. Gene knockout mouse models of Pggt1b have revealed its crucial roles in diseases such as colitis, autoimmunity, and psoriasis-related inflammation, providing insights into the underlying molecular mechanisms and potential therapeutic targets for these diseases [1,2,3,4].

References:

1. López-Posadas, Rocío, Fastancz, Petra, Martínez-Sánchez, Luz Del Carmen, Neurath, Markus F, Atreya, Imke. 2019. Inhibiting PGGT1B Disrupts Function of RHOA, Resulting in T-cell Expression of Integrin α4β7 and Development of Colitis in Mice. In Gastroenterology, 157, 1293-1309. doi:10.1053/j.gastro.2019.07.007. https://pubmed.ncbi.nlm.nih.gov/31302143/

2. Su, Wei, Chapman, Nicole M, Wei, Jun, Vogel, Peter, Chi, Hongbo. 2020. Protein Prenylation Drives Discrete Signaling Programs for the Differentiation and Maintenance of Effector Treg Cells. In Cell metabolism, 32, 996-1011.e7. doi:10.1016/j.cmet.2020.10.022. https://pubmed.ncbi.nlm.nih.gov/33207246/

3. Martínez-Sánchez, Luz Del Carmen, Ngo, Phuong Anh, Pradhan, Rashmita, Neurath, Markus F, López-Posadas, Rocío. 2022. Epithelial RAC1-dependent cytoskeleton dynamics controls cell mechanics, cell shedding and barrier integrity in intestinal inflammation. In Gut, 72, 275-294. doi:10.1136/gutjnl-2021-325520. https://pubmed.ncbi.nlm.nih.gov/35241625/

4. Yu, Shanshan, Wei, Xuecui, Long, Fangyuan, Gu, Heng, Hao, Zhimin. . Quantitative Proteomic Analysis Indicates That Pggt1b Deficiency Promotes Cytokine Secretion in Resiquimod-Stimulated Bone Marrow-Derived Macrophages via the NF-κB Pathway. In Immunity, inflammation and disease, 13, e70185. doi:10.1002/iid3.70185. https://pubmed.ncbi.nlm.nih.gov/40192076/