4.6 Article

Ubiquitin-protein ligase Ubr5 cooperates with hedgehog signalling to promote skeletal tissue homeostasis

期刊

PLOS GENETICS
卷 17, 期 4, 页码 -

出版社

PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1009275

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资金

  1. University of Edinburgh Chancellor's Fellowship
  2. Carnegie Research Incentive Grant [70356]
  3. MRC University Unit [MM_UU_00007/8]
  4. NIH [1R01GM088256]
  5. BBSRC [BB/J004316/1]
  6. MRC [MR/R022240/2]
  7. BBSRC through an Institute Strategic Programme Grant Funding [BB/J004316/1]
  8. BBSRC [BB/S01716X/1] Funding Source: UKRI
  9. MRC [MR/R022240/2] Funding Source: UKRI

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The mammalian Hedgehog (HH) signalling pathway is crucial for tissue homeostasis, with UBR5 being identified as a regulator in maintaining cartilage homeostasis and suppressing metaplasia. Loss of Ubr5 function results in severe articular cartilage degradation, abnormal bone formation, and extensive tissue metaplasia. Additionally, Ubr5 interacts with smoothened to regulate the HH pathway and increase PKA activity, highlighting its important role in musculoskeletal system regulation.
Mammalian Hedgehog (HH) signalling pathway plays an essential role in tissue homeostasis and its deregulation is linked to rheumatological disorders. UBR5 is the mammalian homologue of the E3 ubiquitin-protein ligase Hyd, a negative regulator of the Hh-pathway in Drosophila. To investigate a possible role of UBR5 in regulation of the musculoskeletal system through modulation of mammalian HH signaling, we created a mouse model for specific loss of Ubr5 function in limb bud mesenchyme. Our findings revealed a role for UBR5 in maintaining cartilage homeostasis and suppressing metaplasia. Ubr5 loss of function resulted in progressive and dramatic articular cartilage degradation, enlarged, abnormally shaped sesamoid bones and extensive heterotopic tissue metaplasia linked to calcification of tendons and ossification of synovium. Genetic suppression of smoothened (Smo), a key mediator of HH signalling, dramatically enhanced the Ubr5 mutant phenotype. Analysis of HH signalling in both mouse and cell model systems revealed that loss of Ubr5 stimulated canonical HH-signalling while also increasing PKA activity. In addition, human osteoarthritic samples revealed similar correlations between UBR5 expression, canonical HH signalling and PKA activity markers. Our studies identified a crucial function for the Ubr5 gene in the maintenance of skeletal tissue homeostasis and an unexpected mode of regulation of the HH signalling pathway. Author summary Ubiquitin ligases modify proteins post-translationally which is essential for a variety of cellular processes. UBR5 is an E3 ubiquitin ligase and in Drosophila is a regulator of Hedgehog signaling. In mammals, the Hedgehog (HH) signalling pathway, among many other roles, plays an essential role in tissue maintenance, a process called homeostasis. A murine genetic system was developed to specifically eliminate UBR5 function from embryonic limb tissue that subsequently forms bone and connective tissue (ligaments and tendons). This approach revealed that UBR5 operates as a potent suppressor of excessive growth of normal cartilage and bone and prevents formation of bone in ectopic sites in connective tissue near the knees and ankle joints. In contrast to abnormal growth, UBR5 inhibits degradation of the articular cartilage that cushions the knee joint leading to extensive exposure of underlying bone. Furthermore, Ubr5 interacts with smoothened, a component of the HH pathway, identifying UBR5 as a regulator of mammalian HH signaling in the postnatal musculoskeletal system. In summary, this work shows that UBR5 interacts with the HH pathway to regulate skeletal homeostasis in and around joints of the legs and identifies targets that may be harnessed for biomedical engineering and clinical applications.

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