RHO family proteins are important for the function of inflammatory cells. They are modified with a 20-carbon geranylgeranyl lipid in a process catalyzed by protein geranylgeranyltransferase type I (GGTase-I). Geranylgeranylation is viewed as essential for the membrane targeting and activity of RHO proteins. Consequently, inhibiting GGTase-I to interfere with RHO protein activity has been proposed as a strategy to treat inflammatory disorders. However, here we show that mice lacking GGTase-I in macrophages develop severe joint inflammation resembling erosive rheumatoid arthritis. The disease was initiated by the GGTase-I–deficient macrophages and was transplantable and reversible in bone marrow transplantation experiments. The cells accumulated high levels of active GTP-bound RAC1, CDC42, and RHOA, and RAC1 remained associated with the plasma membrane. Moreover, GGTase-I deficiency activated p38 and NF-κB and increased the production of proinflammatory cytokines. The results challenge the view that geranylgeranylation is essential for the activity and localization of RHO family proteins and suggest that reduced geranylgeranylation in macrophages can initiate erosive arthritis.
Omar M. Khan, Mohamed X. Ibrahim, Ing-Marie Jonsson, Christin Karlsson, Meng Liu, Anna-Karin M. Sjogren, Frida J. Olofsson, Mikael Brisslert, Sofia Andersson, Claes Ohlsson, Lillemor Mattsson Hultén, Maria Bokarewa, Martin O. Bergo
Title and authors | Publication | Year |
---|---|---|
Innate immune training of osteoclastogenesis promotes inflammatory bone loss in mice
Haacke N, Wang H, Yan S, Barovic M, Li X, Nagai K, Botezatu A, Hatzioannou A, Gercken B, Trimaglio G, Shah AU, Wang J, Ye L, Jaykar MT, Rauner M, Wielockx B, Chung KJ, Netea MG, Kalafati L, Hajishengallis G, Chavakis T |
Developmental cell | 2025 |
Protein prenylation in islet β-cell function in health and metabolic stress
Kowluru A |
Biochemical pharmacology | 2025 |
Geranylgeranyl isoprenoids and hepatic Rap1a regulate basal and statin-induced expression of PCSK9.
Wang Y, Tinsley B, Spolitu S, Zadroga JA, Agarwal H, Sarecha AK, Ozcan L |
Journal of lipid research | 2024 |
An alkyne-containing isoprenoid analogue based on a farnesyl diphosphate scaffold is a biologically functional universal probe for proteomic analysis
Auger SA, Pedersen JS, Maity S, Sprague-Getsy AM, Lorimer EL, Koehn OJ, Krauklis SA, Berns B, Murphy KM, Hussain J, Thao P, Bernhagen K, Justyna K, Sundaresan AP, McKim DB, Williams CL, Hougland JL, Li L, Distefano MD |
Biochemistry | 2024 |
GTPase splice variants RAC1 and RAC1B display isoform-specific differences in localization, prenylation, and interaction with the chaperone protein SmgGDS
Koehn OJ, Lorimer E, Unger B, Harris R, Das AS, Suazo KF, Auger SA, Distefano MD, Prokop JW, Williams CL |
The Journal of biological chemistry | 2023 |
Long-term statin therapy is associated with severe coronary artery calcification
Ngamdu KS, Ghosalkar DS, Chung HE, Christensen JL, Lee C, Butler CA, Ho T, Chu A, Heath JR, Baig M, Wu WC, Choudhary G, Morrison AR |
PloS one | 2023 |
Podocyte Geranylgeranyl Transferase Type-I Is Essential for Maintenance of the Glomerular Filtration Barrier
Boi R, Bergwall L, Ebefors K, Bergö MO, Nyström J, Buvall L |
Journal of the American Society of Nephrology : JASN | 2023 |
Metabolic signature and proteasome activity controls synovial migration of CDC42(hi)CD14(+) cells in rheumatoid arthritis.
Malmhäll-Bah E, Andersson KME, Erlandsson MC, Silfverswärd ST, Pullerits R, Bokarewa MI |
Frontiers in immunology | 2023 |
Rho GTPase signaling in rheumatic diseases
R Zeng, Z Zhuo, Y Luo, W Sha, H Chen |
iScience | 2022 |
Targeting cholesterol homeostasis in hematopoietic malignancies
Brendolan A, Russo V |
Blood | 2022 |
Cholesterol metabolism: a new molecular switch to control inflammation
D Cardoso, E Perucha |
Clinical Science | 2021 |
Lipid signalling enforces functional specialization of Treg cells in tumours
SA Lim, J Wei, TL Nguyen, H Shi, W Su, G Palacios, Y Dhungana, NM Chapman, L Long, J Saravia, P Vogel, H Chi |
Nature | 2021 |
Compromised Protein Prenylation as Pathogenic Mechanism in Mevalonate Kinase Deficiency
FA Politiek, HR Waterham |
Frontiers in immunology | 2021 |
Rho GTPase regulation of reactive oxygen species generation and signalling in platelet function and disease
AT Ngo, I Parra-Izquierdo, JE Aslan, OJ McCarty |
Small GTPases | 2021 |
A Requirement of Protein Geranylgeranylation for Chemokine Receptor Signaling and Th17 Cell Function in an Animal Model of Multiple Sclerosis
G Swan, J Geng, E Park, Q Ding, J Zhou, C Walcott, JJ Zhang, HI Huang, GE Hammer, D Wang |
Frontiers in immunology | 2021 |
Rac GTPase Signaling in Immune-Mediated Mechanisms of Atherosclerosis
CF Lee, RE Carley, CA Butler, AR Morrison |
Cells | 2021 |
SmgGDS: An Emerging Master Regulator of Prenylation and Trafficking by Small GTPases in the Ras and Rho Families
AC Brandt, OJ Koehn, CL Williams |
Frontiers in Molecular Biosciences | 2021 |
Targeting the Mevalonate Pathway in Cancer
D Juarez, DA Fruman |
Trends in Cancer | 2021 |
RAC1 Activation as a Potential Therapeutic Option in Metastatic Cutaneous Melanoma
P Colón-Bolea, R García-Gómez, B Casar |
Biomolecules | 2021 |
Serotonin transporter regulation by cholesterol-independent lipid signaling
CM Deveau, E Rodriguez, A Schroering, BK Yamamoto |
Biochemical Pharmacology | 2021 |
Cholesterol metabolism drives regulatory B cell IL-10 through provision of geranylgeranyl pyrophosphate
JA Bibby, HA Purvis, T Hayday, A Chandra, K Okkenhaug, S Rosenzweig, I Aksentijevich, M Wood, HJ Lachmann, C Kemper, AP Cope, E Perucha |
Nature Communications | 2020 |
The balance of protein farnesylation and geranylgeranylation during the progression of nonalcoholic fatty liver disease
Y Zhao, TY Wu, MF Zhao, CJ Li |
The Journal of biological chemistry | 2020 |
Statins Disrupt Macrophage Rac1 Regulation Leading to Increased Atherosclerotic Plaque Calcification
A Healy, JM Berus, JL Christensen, C Lee, C Mantsounga, W Dong, JP Watts, M Assali, N Ceneri, R Nilson, J Neverson, WC Wu, G Choudhary, AR Morrison |
Arteriosclerosis, thrombosis, and vascular biology | 2020 |
Structural modeling, mutation analysis, and in vitro expression of usherin, a major protein in inherited retinal degeneration and hearing loss
D Yu, J Zou, Q Chen, T Zhu, R Sui, J Yang |
Computational and Structural Biotechnology Journal | 2020 |
Role of Macrophages and RhoA Pathway in Atherosclerosis
M Kloc, A Uosef, JZ Kubiak, RM Ghobrial |
International journal of molecular sciences | 2020 |
Systemic Investigation of Promoter-wide Methylome and Genome Variations in Gout
CC Tseng, MC Wong, WT Liao, CJ Chen, SC Lee, JH Yen, SJ Chang |
International journal of molecular sciences | 2020 |
Protein Prenylation Drives Discrete Signaling Programs for the Differentiation and Maintenance of Effector Treg Cells
W Su, NM Chapman, J Wei, H Zeng, Y Dhungana, H Shi, J Saravia, P Zhou, L Long, S Rankin, A KC, P Vogel, H Chi |
Cell Metabolism | 2020 |
RAC1 as a Therapeutic Target in Malignant Melanoma
AC Cannon, C Uribe-Alvarez, J Chernoff |
Trends in Cancer | 2020 |
Scaffold association factor B (SAFB) is required for expression of prenyltransferases and RAS membrane association
M Zhou, L Kuruvilla, X Shi, S Viviano, IM Ahearn, CR Amendola, W Su, S Badri, J Mahaffey, N Fehrenbacher, J Skok, J Schlessinger, BE Turk, DA Calderwood, MR Philips |
Proceedings of the National Academy of Sciences | 2020 |
Control of antiviral innate immune response by protein geranylgeranylation
S Yang, AT Harding, C Sweeney, D Miao, G Swan, C Zhou, Z Jiang, KA Fitzgerald, G Hammer, MO Bergo, HK Kroh, DB Lacy, C Sun, M Glogauer, LG Que, NS Heaton, D Wang |
Science Advances | 2019 |
Protein prenylation restrains innate immunity by inhibiting Rac1 effector interactions
MK Akula, MX Ibrahim, EG Ivarsson, OM Khan, IT Kumar, M Erlandsson, C Karlsson, X Xu, M Brisslert, C Brakebusch, D Wang, M Bokarewa, VI Sayin, MO Bergo |
Nature Communications | 2019 |
Mevalonate metabolism–dependent protein geranylgeranylation regulates thymocyte egress
X Du, H Zeng, S Liu, C Guy, Y Dhungana, G Neale, MO Bergo, H Chi |
Journal of Experimental Medicine | 2019 |
Inhibition of Protein Prenylation of GTPases Alters Endothelial Barrier Function
M Aslam, C Troidl, C Tanislav, S Rohrbach, D Gündüz, CW Hamm |
International journal of molecular sciences | 2019 |
Systemic or Forebrain Neuron-Specific Deficiency of Geranylgeranyltransferase-1 Impairs Synaptic Plasticity and Reduces Dendritic Spine Density
D Hottman, S Cheng, A Gram, K LeBlanc, LL Yuan, L Li |
Neuroscience | 2018 |
RACking up ceramide-induced islet β-cell dysfunction
A Kowluru, RA Kowluru |
Biochemical Pharmacology | 2018 |
Role of G-proteins in islet function in health and diabetes: KOWLURU
A Kowluru |
Diabetes Obesity and Metabolism | 2017 |
Glucotoxicity promotes aberrant activation and mislocalization of Ras-related C3 botulinum toxin substrate 1 [Rac1] and metabolic dysfunction in pancreatic islet β-cells: reversal of such metabolic defects by metformin
S Baidwan, A Chekuri, DA Hynds, A Kowluru |
Apoptosis | 2017 |
Protein prenylation: unique fats make their mark on biology
M Wang, PJ Casey |
Nature Reviews Molecular Cell Biology | 2016 |
Rac2 Modulates Atherosclerotic Calcification by Regulating Macrophage Interleukin-1β ProductionHighlights
N Ceneri, L Zhao, BD Young, A Healy, S Coskun, H Vasavada, TO Yarovinsky, K Ike, R Pardi, L Qin, L Qin, G Tellides, K Hirschi, J Meadows, R Soufer, HJ Chun, MM Sadeghi, JR Bender, AR Morrison |
Arteriosclerosis, thrombosis, and vascular biology | 2016 |
An Interferon Regulated MicroRNA Provides Broad Cell-Intrinsic Antiviral Immunity through Multihit Host-Directed Targeting of the Sterol Pathway
KA Robertson, WY Hsieh, T Forster, M Blanc, H Lu, PJ Crick, E Yutuc, S Watterson, K Martin, SJ Griffiths, AJ Enright, M Yamamoto, MM Pradeepa, KA Lennox, MA Behlke, S Talbot, J Haas, L Dölken, WJ Griffiths, Y Wang, A Angulo, P Ghazal, HL Ploegh |
PLoS Biology | 2016 |
Control of the innate immune response by the mevalonate pathway
MK Akula, M Shi, Z Jiang, CE Foster, D Miao, AS Li, X Zhang, RM Gavin, SD Forde, G Germain, S Carpenter, CV Rosadini, K Gritsman, JJ Chae, R Hampton, N Silverman, EM Gravallese, JC Kagan, KA Fitzgerald, DL Kastner, DT Golenbock, MO Bergo, D Wang |
Nature Immunology | 2016 |
Statins inhibit blastocyst formation by preventing geranylgeranylation
VB Alarcon, Y Marikawa |
Molecular Human Reproduction | 2016 |
Rasd1, a small G protein with a big role in the hypothalamic response to neuronal activation
MP Greenwood, M Greenwood, AS Mecawi, J Antunes-Rodrigues, JF Paton, D Murphy |
Molecular brain | 2016 |
Metabolic Stress Induces Caspase-3 Mediated Degradation and Inactivation of Farnesyl and Geranylgeranyl Transferase Activities in Pancreatic β-Cells
R Veluthakal, DK Arora, ML Goalstone, RA Kowluru, A Kowluru |
Cellular Physiology and Biochemistry | 2016 |
Targeting the isoprenoid pathway to abrogate progression Of pulmonary fibrosis
HL Osborn-Heaford, S Murthy, L Gu, JL Larson-Casey, AJ Ryan, L Shi, M Glogauer, JD Neighbors, R Hohl, AB Carter |
Free radical biology & medicine | 2015 |
The Role of Geranylgeranyltransferase I-Mediated Protein Prenylation in the Brain
S Gao, R Yu, X Zhou |
Molecular Neurobiology | 2015 |
Protein prenylation in islet β-cell function in health and diabetes: Putting the pieces of the puzzle together
A Kowluru, RA Kowluru |
Biochemical Pharmacology | 2015 |
Phagocyte-like NADPH oxidase (Nox2) promotes activation of p38MAPK in pancreatic β-cells under glucotoxic conditions: Evidence for a requisite role of Ras-related C3 botulinum toxin substrate 1 (Rac1)
V Sidarala, R Veluthakal, K Syeda, C Vlaar, P Newsholme, A Kowluru |
Biochemical Pharmacology | 2015 |
Use of synthetic isoprenoids to target protein prenylation and Rho GTPases in breast cancer invasion
M Chen, T Knifley, T Subramanian, HP Spielmann, KL O'Connor |
PloS one | 2014 |
Role of the Rho GTPase Rac in the activation of the phagocyte NADPH oxidase: Outsourcing a key task
E Pick |
Small GTPases | 2014 |
Etanercept Administration to Neonatal SH3BP2 Knock-In Cherubism Mice Prevents TNF-α-Induced Inflammation and Bone Loss
T Yoshitaka, S Ishida, T Mukai, M Kittaka, EJ Reichenberger, Y Ueki |
Journal of Bone and Mineral Research | 2014 |
Targeting GGTase-I activates RHOA, increases macrophage reverse cholesterol transport, and reduces atherosclerosis in mice
OM Khan, MK Akula, K Skålen, C Karlsson, M Ståhlman, SG Young, J Borén, MO Bergo |
Circulation | 2013 |
Altered protein prenylation in Sertoli cells is associated with adult infertility resulting from childhood mumps infection
XX Wang, P Ying, F Diao, Q Wang, D Ye, C Jiang, N Shen, N Xu, WB Chen, SS Lai, S Jiang, XL Miao, J Feng, WW Tao, NW Zhao, B Yao, ZP Xu, HX Sun, JM Li, JH Sha, XX Huang, QH Shi, H Tang, X Gao, CJ Li |
Journal of Experimental Medicine | 2013 |
In vitro and in vivo effects of geranylgeranyltransferase I inhibitor P61A6 on non-small cell lung cancer cells
DB Zimonjic, LN Chan, V Tripathi, J Lu, O Kwon, NC Popescu, DR Lowy, F Tamanoi |
BMC Cancer | 2013 |
An Adenosine-Mediated Signaling Pathway Suppresses Prenylation of the GTPase Rap1B and Promotes Cell Scattering
E Ntantie, P Gonyo, EL Lorimer, AD Hauser, N Schuld, D McAllister, B Kalyanaraman, MB Dwinell, JA Auchampach, CL Williams |
Science signaling | 2013 |
Deciphering the signaling networks underlying simvastatin-induced apoptosis in human cancer cells: evidence for non-canonical activation of RhoA and Rac1 GTPases
Y Zhu, PJ Casey, AP Kumar, S Pervaiz |
Cell Death and Disease | 2013 |
Farnesyltransferase Haplodeficiency Reduces Neuropathology and Rescues Cognitive Function in a Mouse Model of Alzheimer Disease
S Cheng, D Cao, DA Hottman, L Yuan, MO Bergo, L Li |
The Journal of biological chemistry | 2013 |
Sufficient production of geranylgeraniol is required to maintain endotoxin tolerance in macrophages
J Kim, JN Lee, J Ye, R Hao, R DeBose-Boyd, J Ye |
Journal of lipid research | 2013 |
Rho-kinase: regulation, (dys)function, and inhibition
E Amin, BN Dubey, SC Zhang, L Gremer, R Dvorsky, JM Moll, MS Taha, L Nagel-Steger, RP Piekorz, AV Somlyo, MR Ahmadian |
Biological Chemistry | 2013 |
Rac function is critical for cell migration but not required for spreading and focal adhesion formation
A Steffen, M Ladwein, GA Dimchev, A Hein, L Schwenkmezger, S Arens, KI Ladwein, JM Holleboom, F Schur, JV Small, J Schwarz, R Gerhard, J Faix, TE Stradal, C Brakebusch, K Rottner |
Journal of cell science | 2013 |
Rac-ing to the plasma membrane
XR Bustelo, V Ojeda, M Barreira, V Sauzeau, A Castro-Castro |
Small GTPases | 2012 |
Protein disulfide isomerase is required for platelet-derived growth factor-induced vascular smooth muscle cell migration, Nox1 NADPH oxidase expression, and RhoGTPase activation
LA Pescatore, D Bonatto, FL Forti, A Sadok, H Kovacic, FR Laurindo |
The Journal of biological chemistry | 2012 |
The perplexing case of the geranylgeranyl transferase–deficient mouse
Mark R Philips |
Journal of Clinical Investigation | 2011 |
Severe hepatocellular disease in mice lacking one or both CaaX prenyltransferases
SH Yang, SY Chang, Y Tu, GW Lawson, MO Bergo, LG Fong, SG Young |
Journal of lipid research | 2011 |
Pulmonary surfactant: an immunological perspective
ZC Chroneos, Z Sever-Chroneos, VL Shepherd |
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology | 2009 |