Serine-threonine kinase ROCK2 regulates germinal center B cell positioning and cholesterol biosynthesis

Ricker, Edd; Chinenov, Yurii; Pannellini, Tania; Flores-Castro, Danny; Ye, Chao; Manni, Michela; Liao, James K.; Pernis, Alessandra B.

doi:10.1172/jci132414

Cited by 29 publications

(33 citation statements)

References 62 publications

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“…Rock1 (the isozyme of Rock2, with 93% kinase domain homology) (33), did not pass the initial stringent filtering of primary whole genome siRNA screen data (mean z cilia = +0.864), although siRNA knockdown had a marginal positive effect on cilia incidence that is consistent with the results in a previous siRNA screen of "druggable targets" (34). Since fasudil is a broadly selective inhibitor of both ROCK isozymes, it was important to determine which isozyme had the predominant effect on ciliogenesis since they both have distinct and separate functional roles in other cellular mechanisms (35)(36)(37)(38). We hypothesised that ROCK1 has a redundant role in ciliogenesis because residual ROCK1 activity had not been able to compensate for the loss of ROCK2 in our previous experiments.…”

Section: Rock1 Cannot Compensate For Loss Of Rock2 Function During CIsupporting

confidence: 76%

Drug and siRNA screens identify ROCK2 as a therapeutic target for ciliopathies

Lake¹,

Smith²,

Natarajan³

et al. 2020

Preprint

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Primary cilia are microtubule-based organelles that act as cellular antennae to mediate vertebrate development and growth factor signalling. Defects in primary cilia result in a group of inherited developmental conditions known as ciliopathies. Ciliopathies often present with cystic kidney disease, a major cause of early renal failure that requires renal replacement therapies. Currently, only one drug, Tolvaptan, is licensed to slow the decline of renal function for the ciliopathy polycystic kidney disease. Novel therapeutic interventions for these conditions remain a pressing clinical need.We screened clinical development compounds for positive effects on cilia formation and function and identified fasudil hydrochloride as the top hit. Fasudil is a generic, off-patent drug that is a potent but broadly selective Rho-associated coiled-coil-containing protein kinase (ROCK) inhibitor. In a parallel whole genome siRNA-based reverse genetics phenotypic screen of positive modulators of cilia formation, we identified ROCK2 as the target molecule. We demonstrate that ROCK2 is a key mediator of cilium formation and function through effects on actin cytoskeleton remodelling. Our results indicate that specific ROCK2 inhibitors such as belumosudil (KD-025) could be repurposed for pharmacological intervention in cystic kidney disease. We propose that ROCK2 inhibition represents a novel, disease-modifying therapeutic approach for heterogeneous ciliopathies.

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Section: Rock1 Cannot Compensate For Loss Of Rock2 Function During CIsupporting

confidence: 76%

Drug and siRNA screens identify ROCK2 as a therapeutic target for ciliopathies

Lake¹,

Smith²,

Natarajan³

et al. 2020

Preprint

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“…The pairing of IRF5 with IRF8 in this compartment may provide ABCs and their CD11c + progeny with a more "innate" quality than traditional CD11c -B cell subsets and facilitate their distinctive combination of innate and adaptive functions. Changes in IRF8 activity, like those mediated by ROCK2 phosphorylation 50 , could instead result in the downregulation of typical ABC transcriptional targets like CD11c and help promote its interaction with other transactivators enabling ABCs to give rise to both CD11c + and CD11ceffector progeny. In support of this notion preliminary studies indicate that TLR7 engagement can inhibit ROCK2 activation thus directly affecting this balance.…”

Section: Discussionmentioning

confidence: 99%

Sex-specific differences in the function and differentiation of ABCs mark TLR7-driven immunopathogenesis

Ricker

Manni

Flores-Castro

et al. 2021

Preprint

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Sex differences characterize immune responses to viruses like SARS-CoV2 and autoimmune diseases like SLE. ABCs are an emerging population of CD11c+ T-bet+ B cells critical for antiviral responses and autoimmune disorders. DEF6 and SWAP70, are two homologous molecules whose combined absence in double-knock-out mice (DKOs) leads to a lupus syndrome in females marked by an accumulation of ABCs. Here we demonstrate that DKO ABCs exhibit sex-specific differences in their expansion, upregulation of an ISG signature, and further differentiation. BCR sequencing and fate mapping experiments reveal that DKO ABCs undergo oligoclonal expansion and differentiate into both CD11c+ and CD11c− effector populations with pathogenic and proinflammatory potential. Tlr7 duplication in DKO males overrides the sex-bias and further augments the dissemination and pathogenicity of ABCs resulting in severe pulmonary inflammation and early mortality. Thus, sexual dimorphism shapes the expansion, function, and differentiation of ABCs contributing to the sex-bias that accompanies TLR7-driven immunopathogenesis.

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“…Initial insights linking ROCK2 to diseases were gleaned from studies implicating ROCK2 as a regulator of, among others, immunity, inflammation, and fibrosis (Yang et al, 2018;Stam et al, 2019;Ricker et al, 2020). With regard to the kidney, we provided the first evidence indicating ROCK2 to be a core component of signaling circuitry that governs DKD progression.…”

Section: Rock2-induced Fibrosis Notch Activation and Inflammation Imentioning

confidence: 94%

The Physiology, Pathology, and Therapeutic Interventions for ROCK Isoforms in Diabetic Kidney Disease

et al. 2020

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Rho-associated coiled-coil-containing protein kinase (ROCK) is a serine/threonine kinase that was originally identified as RhoA interacting protein. A diverse array of cellular functions, including migration, proliferation, and phenotypic modulation, are orchestrated by ROCK through a mechanism involving cytoskeletal rearrangement. Mammalian cells express two ROCK isoforms: ROCK1 (Rho-kinase b/ROKb) and ROCK2 (Rho-kinase a/ROKa). While both isoforms have structural similarities and are widely expressed across multiple tissues, investigations in gene knockout animals and cell-based studies have revealed distinct functions of ROCK1 and ROCK2. With respect to the kidney, inhibiting ROCK activity has proven effective for the preventing diabetic kidney disease (DKD) in both type 1 and type 2 diabetic rodent models. However, despite significant progress in the understanding of the renal ROCK biology over the past decade, the pathogenic roles of the ROCK isoforms is only beginning to be elucidated. Recent studies have demonstrated the involvement of renal ROCK1 in mitochondrial dynamics and cellular transdifferentiation, whereas ROCK2 activation leads to inflammation, fibrosis, and cell death in the diabetic kidney. This review provides a conceptual framework for dissecting the molecular underpinnings of ROCKdriven renal injury, focusing on the differences between ROCK1 and ROCK2.

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Serine-threonine kinase ROCK2 regulates germinal center B cell positioning and cholesterol biosynthesis

Cited by 29 publications

References 62 publications

Drug and siRNA screens identify ROCK2 as a therapeutic target for ciliopathies

Drug and siRNA screens identify ROCK2 as a therapeutic target for ciliopathies

Sex-specific differences in the function and differentiation of ABCs mark TLR7-driven immunopathogenesis

The Physiology, Pathology, and Therapeutic Interventions for ROCK Isoforms in Diabetic Kidney Disease

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