Ubiquitin ligase RNF146 coordinates bone dynamics and energy metabolism

Matsumoto, Yoshinori; Rose, José La; Lim, Melissa; Adissu, Hibret A.; Law, Napoleon; Mao, Xiaohong; Cong, Feng; Mera, Paula; Karsenty, G.; Goltzman, David; Changoor, Adele; Zhang, Lucia; Stajkowski, Megan; Grynpas, Marc D.; Bergmann, Carsten; Rottapel, Robert

doi:10.1172/jci92233

Cited by 40 publications

(44 citation statements)

References 41 publications

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“…For instance, PTH(7-34) accumulates to high levels in end-stage kidney disease (5). Further, ubiquitin ligase RNF146 has been implicated in cleidocranial dysplasia (CCD), an autosomal dominant for of abnormal bone disease (76). Moreover, PTH-induced osteoblast proliferation requires direct regulation of the ubiquitin-specific-processing protease 2 gene, USP2 (77), which we demonstrated is required for PTHR deubiquitination (19).…”

Section: Discussionmentioning

confidence: 68%

Site-specific polyubiquitination differentially regulates parathyroid hormone receptor–initiated MAPK signaling and cell proliferation

Zhang¹,

Xiao²,

Liu³

et al. 2018

Journal of Biological Chemistry

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G protein-coupled receptor (GPCR) signaling and trafficking are essential for cellular function and regulated by phosphorylation, β-arrestin, and ubiquitination. The GPCR parathyroid hormone receptor (PTHR) exhibits time-dependent reversible ubiquitination. The exact ubiquitination sites in PTHR are unknown, but extend upstream of its intracellular tail. Here, using tandem MS, we identified Lys-388 in the third loop and Lys-484 in the C-terminal tail as primary ubiquitination sites in PTHR. We found that PTHR ubiquitination requires β-arrestin and does not display a preference for β-arrestin1 or 2. PTH stimulated PTHR phosphorylation at Thr-387/Thr-392 and within the Ser-489/Ser-493 region. Such phosphorylation events may recruit β-arrestin, and we observed that chemically or genetically blocking PTHR phosphorylation inhibits its ubiquitination. Specifically, Ala replacement at Thr-387/Thr-392 suppressed β-arrestin binding and inhibited PTHR ubiquitination, suggesting that PTHR phosphorylation and ubiquitination are interdependent. Of note, Lysdeficient PTHR mutants promoted normal cAMP formation, but exhibited differential mitogenactivated protein kinase (MAPK) signaling. Lysdeficient PTHR triggered early onset and delayed ERK1/2 signaling compared with wild-type PTHR. Moreover, ubiquitination of Lys-388 and Lys-484 in wild-type PTHR strongly decreased p38 signaling, whereas Lys-deficient PTHR retained signaling comparable to unstimulated wild-type PTHR. Lysdeficient, ubiquitination-refractory PTHR reduced cell proliferation and increased apoptosis. However, elimination of all 11 Lys residues in PTHR did not affect its internalization and recycling. These results pinpoint the ubiquitinated Lys residues in PTHR controlling MAPK signaling and cell proliferation and survival. Our findings suggest new opportunities for targeting PTHR ubiquitination to regulate MAPK signaling or manage PTHR-related disorders.

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Section: Discussionmentioning

confidence: 68%

Site-specific polyubiquitination differentially regulates parathyroid hormone receptor–initiated MAPK signaling and cell proliferation

Zhang¹,

Xiao²,

Liu³

et al. 2018

Journal of Biological Chemistry

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“…These results may also have implications for the regulation of this highly conserved pathway in mammals. For example, conditional inactivation of Iduna in mouse bones leads to increased numbers of osteoclasts and inflammation (Matsumoto et al, 2017a). In this system, downregulation of Iduna leads to accumulation of Axin1 and 3BP2 (Sh3bp2).…”

Section: Discussionmentioning

confidence: 99%

“…In this system, downregulation of Iduna leads to accumulation of Axin1 and 3BP2 (Sh3bp2). This, in turn, attenuates β-catenin degradation and activates SRC kinase, respectively, thereby promoting the release of inflammatory cytokines in the bone (Matsumoto et al, 2017a). Iduna depletion reduces proliferation of osteoblasts and promotes adipogenesis in the mouse skeleton (Matsumoto et al, 2017b).…”

Section: Discussionmentioning

confidence: 99%

Axin proteolysis by Iduna is required for the regulation of stem cell proliferation and intestinal homeostasis in Drosophila

Gültekin

Steller

2019

Development

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Self-renewal of intestinal stem cells is controlled by Wingless/Wnt-β catenin signaling in both Drosophila and mammals. As Axin is a rate-limiting factor in Wingless signaling, its regulation is essential. Iduna is an evolutionarily conserved ubiquitin E3 ligase that has been identified as a crucial regulator for degradation of ADP-ribosylated Axin and, thus, of Wnt/β-catenin signaling. However, its physiological significance remains to be demonstrated. Here, we generated loss-offunction mutants of Iduna to investigate its physiological role in Drosophila. Genetic depletion of Iduna causes the accumulation of both Tankyrase and Axin. Increase of Axin protein in enterocytes non-autonomously enhanced stem cell divisions in the Drosophila midgut. Enterocytes secreted Unpaired proteins and thereby stimulated the activity of the JAK-STAT pathway in intestinal stem cells. A decrease in Axin gene expression suppressed the over-proliferation of stem cells and restored their numbers to normal levels in Iduna mutants. These findings suggest that Iduna-mediated regulation of Axin proteolysis is essential for tissue homeostasis in the Drosophila midgut.

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“…The above findings demonstrated that RNF146 is a mesenchymal fate-determining factor required for the development of the osteoblast lineage while antagonizing adipocyte differentiation. These results provided the basis for the molecular mechanism by which hypoplastic bone formation causes abnormal energy metabolism [30].…”

Section: Rnf146 and Osteoblastogenesismentioning

confidence: 92%

“…Our results revealed that loss of RNF146 results in a dysregulated signaling pathway characterized by inhibition of b-catenin activity caused by stabilization of AXIN1 and downregulated expression of fibroblast growth factor 18 (Fgf18), which is required for TAZ protein expression and subsequent RUNX2 activation. FGF18 upregulates TAZ expression by activating the MAPK pathway, and defective proliferation and mineralization observed in RNF146-null osteoblasts can be rescued by treatment with exogenous FGF18, demonstrating that RNF146 is critical for normal embryonic and postnatal bone formation and acts by regulating the Wnt-FGF18-TAZ-RUNX2 pathway [30]. Therefore, loss-of-function mutations in the RNF146 gene are likely to be involved in the pathogenesis of CCD in humans.…”

Section: Rnf146 and Osteoblastogenesismentioning

confidence: 99%

Bone dynamics and inflammation: lessons from rare diseases

Matsumoto

Rottapel

2020

Immunological Medicine

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The adaptor protein 3BP2 (SH3-domain binding protein 2), which is encoded by the SH3BP2 locus, nucleates a signaling complex comprising ABL, SRC, VAV, and SYK, and facilitates an open active configuration of these proteins, leading to their kinase activation. Gain-of-function missense mutations in the SH3BP2 gene cause cherubism, an autosomal dominant disorder associated with severe craniofacial developmental defects in children. Previous studies have demonstrated that 3BP2 and its degradation pathway regulate bone metabolism, energy metabolism, and inflammation and that dysregulation of the 3BP2 degradation pathway is associated with human disorders. Herein, we discussed lessons from cherubism indicating that 3BP2 studies could elucidate the pathogenesis of bone loss caused by inflammation and identify suitable therapeutic targets.

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Ubiquitin ligase RNF146 coordinates bone dynamics and energy metabolism

Cited by 40 publications

References 41 publications

Site-specific polyubiquitination differentially regulates parathyroid hormone receptor–initiated MAPK signaling and cell proliferation

Site-specific polyubiquitination differentially regulates parathyroid hormone receptor–initiated MAPK signaling and cell proliferation

Axin proteolysis by Iduna is required for the regulation of stem cell proliferation and intestinal homeostasis in Drosophila

Bone dynamics and inflammation: lessons from rare diseases

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