TY - JOUR
T1 - Poly-ADP-ribosylation-mediated degradation of ARTD1 by the NLRP3 inflammasome is a prerequisite for osteoclast maturation
AU - Wang, C.
AU - Qu, C.
AU - Alippe, Y.
AU - Bonar, S. L.
AU - Civitelli, R.
AU - Abu-Amer, Y.
AU - Hottiger, M. O.
AU - Mbalaviele, G.
N1 - Funding Information:
We thank Jacqueline Kading for maintaining mouse colonies. We also thank the Musculoskeletal Histology and Morphometry Core as well as the Structure and Strength Core at Washington University in St. Louis. This work was supported by NIH/NIAMS R01-AR064755 grant to GM and the 5 P30 AR057235 NIH/Core Center for Musculoskeletal Biology and Medicine to GM. YA is supported by AR-054326 grant, and ADP-ribosylation research in the laboratory of MOH is funded by the Kanton of Zurich and the Swiss National Science Foundation (grant 310030B_138667).
Funding Information:
G.M. is co-founder of Confluence Life Sciences. R.C. receives research support from Pfizer, Inc. and Amgen, and holds stock of Amgen, Eli-Lilly and Merck & Co. The remaining authors declare no conflict of interest.
Funding Information:
Acknowledgements. We thank Jacqueline Kading for maintaining mouse colonies. We also thank the Musculoskeletal Histology and Morphometry Core as well as the Structure and Strength Core at Washington University in St. Louis. This work was supported by NIH/NIAMS R01-AR064755 grant to GM and the 5 P30 AR057235 NIH/Core Center for Musculoskeletal Biology and Medicine to GM. YA is supported by AR-054326 grant, and ADP-ribosylation research in the laboratory of MOH is funded by the Kanton of Zurich and the Swiss National Science Foundation (grant 310030B_138667).
Publisher Copyright:
© 2016, Macmillan Publishers Limited. All rights reserved.
PY - 2016
Y1 - 2016
N2 - Evidence implicates ARTD1 in cell differentiation, but its role in skeletal metabolism remains unknown. Osteoclasts (OC), the bone-resorbing cells, differentiate from macrophages under the influence of macrophage colony-stimulating factor (M-CSF) and receptor-activator of NF-κB ligand (RANKL). We found that M-CSF induced ADP-ribosyltransferase diphtheria toxin-like 1 (ARTD1) auto-ADP-ribosylation in macrophages, a modification that marked ARTD1 for cleavage, and subsequently, for degradation upon RANKL exposure. We established that ARTD1 proteolysis was NLRP3 inflammasome-dependent, and occurred via the proteasome pathway. Since ARTD1 is cleaved at aspartate214, we studied the impact of ARTD1 rendered uncleavable by D214N substitution (ARTD1D214N ) on skeletal homeostasis. ARTD1D214N, unlike wild-type ARTD1, was resistant to cleavage and degradation during osteoclastogenesis. As a result, ARTD1D214N altered histone modification and promoted the abundance of the repressors of osteoclastogenesis by interfering with the expression of B lymphocyte-induced maturation protein 1 (Blimp1), the master regulator of anti-osteoclastogenic transcription factors. Importantly, ARTD1D214N-expressing mice exhibited higher bone mass compared with controls, owing to decreased osteoclastogenesis while bone formation was unaffected. Thus, unless it is degraded, ARTD1 represses OC development through transcriptional regulation.
AB - Evidence implicates ARTD1 in cell differentiation, but its role in skeletal metabolism remains unknown. Osteoclasts (OC), the bone-resorbing cells, differentiate from macrophages under the influence of macrophage colony-stimulating factor (M-CSF) and receptor-activator of NF-κB ligand (RANKL). We found that M-CSF induced ADP-ribosyltransferase diphtheria toxin-like 1 (ARTD1) auto-ADP-ribosylation in macrophages, a modification that marked ARTD1 for cleavage, and subsequently, for degradation upon RANKL exposure. We established that ARTD1 proteolysis was NLRP3 inflammasome-dependent, and occurred via the proteasome pathway. Since ARTD1 is cleaved at aspartate214, we studied the impact of ARTD1 rendered uncleavable by D214N substitution (ARTD1D214N ) on skeletal homeostasis. ARTD1D214N, unlike wild-type ARTD1, was resistant to cleavage and degradation during osteoclastogenesis. As a result, ARTD1D214N altered histone modification and promoted the abundance of the repressors of osteoclastogenesis by interfering with the expression of B lymphocyte-induced maturation protein 1 (Blimp1), the master regulator of anti-osteoclastogenic transcription factors. Importantly, ARTD1D214N-expressing mice exhibited higher bone mass compared with controls, owing to decreased osteoclastogenesis while bone formation was unaffected. Thus, unless it is degraded, ARTD1 represses OC development through transcriptional regulation.
UR - http://www.scopus.com/inward/record.url?scp=84979499463&partnerID=8YFLogxK
U2 - 10.1038/cddis.2016.58
DO - 10.1038/cddis.2016.58
M3 - Article
C2 - 27010854
AN - SCOPUS:84979499463
VL - 7
JO - Cell Death and Disease
JF - Cell Death and Disease
SN - 2041-4889
IS - 3
M1 - e2153
ER -