Year: 2019
Type: dissertation
Abstract: CAAX proteins are a group of proteins that undergo a three-step protein maturation process that\nrenders the proteins carboxyl-terminus hydrophobic and prone to localize to cellular membranes,\nwhere they have their primary function. The first step in this process is called prenylation, which\nis the covalent attachment of a lipid, either a 15-carbon farnesyl or a 20-carbon geranylgeranyl\nlipid, to the carboxyl-terminal cysteine residue by the enzymes farnesyltransferase (FTase) and\ngeranylgeranyltransferase type I (GGTase-I), respectively.\nStatins are inhibitors of HMG-CoA reductase, the rate-limiting enzyme in the cholesterol\nbiosynthesis pathway, and are widely used in the treatment of hypercholesterolemia. They are\nthought to improve myocardial function by inhibiting GGTase-I- and FTase-mediated prenylation\nof the CAAX proteins RHOA and RAC1, two known mediators of cardiomyopathy. In the first\npaper of this thesis, we show that, contrary to popular belief, long-term statin administration\ncauses reduced heart function, hypertrophic cardiomyopathy, and hyperactive RHOA in the\nhearts of wild-type mice. Similarly, we show that inactivation of the prenylation enzymes\nGGTase-I, FTase, or both, in heart muscle cells causes severe dilated cardiomyopathy. These\nfindings indicate that statins and prenylation inhibitors might have the capacity to cause heart\nproblems.\nIn the second paper, we define the mechanism underlying a previous finding that inactivation of\nGGTase-I in mouse macrophages prevents prenylation of RHO family proteins, paradoxically\ncauses them to become hyperactive, and that this leads to severe rheumatoid arthritis. We find\nthat the RHO-protein RAC1 is responsible for the development of rheumatoid arthiritis. We\nfurther show that non-prenylated RAC1 exhibit an increased interaction with the effector proteins\nTIAM1 and IQGAP1 which trigger GTP loading, activation, excessive inflammatory signaling,\nand arthritis. Inactivation of RAC1 or IQGAP1 reduces the inflammatory signaling and markedly\nimproves rheumatoid arthritis in GGTase-I deficient mice. We conclude that inhibiting\nprenylation of RAC1 stimulates effector interactions and cause excessive inflammatory signaling.\nThis finding suggests that prenylation normally restrains innate immunity by limiting RAC1\neffector interactions and its activation.\nProtein-altering germline mutations are a major cause of dilated cardiomyopathy (DCM).\nHowever, recent sequencing studies have shown that rare protein-altering variants are also\npresent in individuals without reported DCM. This complicates the interpretation of genetic\ntesting in the clinic, which is increasingly used for diagnosis. In the third paper, we analyzed\ngenotype-phenotype correlations and variant prevalence in 41 DCM-associated genes in a cohort\nof 176 Swedish DCM patients, and compared the variants to those of healthy reference\nindividuals. We found 102 rare protein-altering variants, many of which were not previously\nreported, and further analysis revealed that harboring any variant was correlated with earlier\nonset of disease and reduced transplant-free survival. Comparing the number of variants found\nin DCM patients to rare variants in a healthy population showed that, while frameshift and\nnonsense variant were more common in DCM patients, the prevalence, pathogenicity scores,\nand location of missense variants were similar in both groups. These findings question the role\nof many putatively disease-causing variants and suggest that results from genetic testing should\nbe interpreted with caution.
Author: Emil G. Ivarsson
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2973875241