Atypical cell death and insufficient matrix organization in long-bone growth plates from Tric-b-knockout mice

1. Fink RH, Veigel C. Calcium uptake and release modulated by counter-ion conductances in the sarcoplasmic reticulum of skeletal muscle. Acta Physiol Scand.

1996;156:387–96.

2. Meissner G. Monovalent ion and calcium ion fluxes in sarcoplasmic reticulum.

Mol Cell Biochem. 1983;55:65–82.

3. Somlyo AV, Gonzalez-Serratos HG, Shuman H, McClellan G, Somlyo AP. Calcium

release and ionic changes in the sarcoplasmic reticulum of tetanized muscle: an

electron-probe study. J Cell Biol. 1981;90:577–94.

4. Coronado R, Miller C. Decamethonium and hexamethonium block K+ channels of

sarcoplasmic reticulum. Nature. 1980;288:495–7.

5. Ide T, Sakamoto H, Morita T, Taguchi T, Kasai M. Purification of a Cl− channel

protein of sarcoplasmic reticulum by assaying the channel activity in the planar

lipid bilayer system. Biochem Biophys Res Commun. 1991;176:38–44.

6. Kamp F, Donoso P, Hidalgo C. Changes in luminal pH caused by calcium release

in sarcoplasmic reticulum vesicles. Biophys J. 1998;74:290–6.

7. Pitt SJ, Park K-H, Nishi M, Urashima T, Aoki S, Yamazaki D, et al. Charade of the SR

K+-channel: two ion-channels, TRIC-A and TRIC-B, masquerade as a single

K+-channel. Biophys J. 2010;99:417–26.

8. Venturi E, Matyjaszkiewicz A, Pitt SJ, Tsaneva-Atanasova K, Nishi M, Yamazaki D,

et al. TRIC-B channels display labile gating: evidence from the TRIC-A knockout

mouse model. Pflugers Arch. 2013;465:1135–48.

9. Yazawa M, Ferrante C, Feng J, Mio K, Ogura T, Zhang M, et al. TRIC channels are

essential for Ca2+ handling in intracellular stores. Nature. 2007;448:78–82.

10. Kasuya G, Hiraizumi M, Maturana AD, Kumazaki K, Fujiwara Y, Liu K, et al. Crystal

structures of the TRIC trimeric intracellular cation channel orthologues. Cell Res.

2016;26:1288–301.

11. Wang X-h, Su M, Gao F, Xie W, Zeng Y, Li D-l, et al. Structural basis for activity of

TRIC counter-ion channels in calcium release. Proc Natl Acad Sci.

2019;116:4238–43.

12. Yang H, Hu M, Guo J, Ou X, Cai T, Liu Z. Pore architecture of TRIC channels and

insights into their gating mechanism. Nature. 2016;538:537–41.

13. Zhao X, Yamazaki D, Park KH, Komazaki S, Tjondrokoesoemo A, Nishi M, et al.

Ca2+ overload and sarcoplasmic reticulum instability in tric-a null skeletal muscle.

J Biol Chem. 2010;285:37370–6.

14. Yamazaki D, Tabara Y, Kita S, Hanada H, Komazaki S, Naitou D, et al. TRIC-A

channels in vascular smooth muscle contribute to blood pressure maintenance.

Cell Metab. 2011;14:231–41.

15. Yamazaki D, Komazaki S, Nakanishi H, Mishima A, Nishi M, Yazawa M, et al.

Essential role of the TRIC-B channel in Ca2+ handling of alveolar epithelial cells

and in perinatal lung maturation. Development. 2009;136:2355–61.

Cell Death and Disease (2023)14:848

A. Ichimura et al.

11

16. Zhao C, Ichimura A, Qian N, Iida T, Yamazaki D, Noma N, et al. Mice lacking the

intracellular cation channel TRIC-B have compromised collagen production and

impaired bone mineralization. Sci Signal. 2016;9:ra49.

17. Zhou X, Park KH, Yamazaki D, Lin P-h, Nishi M, Ma Z, et al. TRIC-A channel

maintains store calcium handling by interacting with type 2 ryanodine receptor

in cardiac muscle. Circ Res. 2020;126:417–35.

18. Berendsen AD, Olsen BR. Bone development. Bone. 2015;80:14–18.

19. Byers PH, Pyott SM. Recessively inherited forms of osteogenesis imperfecta. Ann

Rev Genet. 2012;46:475–97.

20. Lv F, Xu X-J, Wang J-Y, Liu Y, Asan, Wang J-W, et al. Two novel mutations in

TMEM38B result in rare autosomal recessive osteogenesis imperfecta. J Hum

Genet. 2016;61:539–45.

21. Rubinato E, Morgan A, D’Eustacchio A, Pecile V, Gortani G, Gasparini P, et al. A

novel deletion mutation involving TMEM38B in a patient with autosomal recessive osteogenesis imperfecta. Gene. 2014;545:290–2.

22. Volodarsky M, Markus B, Cohen I, Staretz-Chacham O, Flusser H, Landau D, et al. A

deletion mutation in TMEM38B associated with autosomal recessive osteogenesis

imperfecta. Hum Mutation. 2013;34:582–6.

23. Shaheen R, Alazami AM, Alshammari MJ, Faqeih E, Alhashmi N, Mousa N, et al.

Study of autosomal recessive osteogenesis imperfecta in Arabia reveals a novel

locus defined by TMEM38B mutation. J Med Genet. 2012;49:630–5.

24. Bateman JF, Cabral WA, Ishikawa M, Garten M, Makareeva EN, Sargent BM, et al.

Absence of the ER cation channel TMEM38B/TRIC-B disrupts intracellular calcium

homeostasis and dysregulates collagen synthesis in recessive osteogenesis

imperfecta. PLOS Genetics. 2016;12:e1006156.

25. Hetz C, Zhang K, Kaufman RJ. Mechanisms, regulation and functions of the

unfolded protein response. Nat Rev Mol Cell Biol. 2020;21:421–38.

26. Mungrue IN, Pagnon J, Kohannim O, Gargalovic PS, Lusis AJ. CHAC1/MGC4504 is

a novel proapoptotic component of the unfolded protein response, downstream

of the ATF4-ATF3-CHOP cascade. J Immunol. 2009;182:466–176.

27. Sadighi Akha AA, Harper JM, Salmon AB, Schroeder BA, Tyra HM, Rutkowski DT,

et al. Heightened induction of proapoptotic signals in response to endoplasmic

reticulum stress in primary fibroblasts from a mouse model of longevity. J Biol

Chem. 2011;286:30344–51.

28. Kokame K, Kato H, Miyata T. Identification of ERSE-II, a New cis-acting element

responsible for the ATF6-dependent mammalian unfolded protein response. J

Biol Chem. 2001;276:9199–205.

29. Saito A, Hino S-i, Murakami T, Kanemoto S, Kondo S, Saitoh M, et al. Regulation of

endoplasmic reticulum stress response by a BBF2H7-mediated Sec23a pathway is

essential for chondrogenesis. Nat Cell Biol. 2009;11:1197–204.

30. Kesavardhana S, Malireddi RKS, Kanneganti T-D. Caspases in cell death, inflammation, and pyroptosis. Annu Rev Immunol. 2020;38:567–295.

31. Qian N, Ichimura A, Takei D, Sakaguchi R, Kitani A, Nagaoka R, et al. TRPM7

channels mediate spontaneous Ca2+ fluctuations in growth plate chondrocytes

that promote bone development. Sci Signal. 2019;12:eaaw4847.

32. Lupoli TJ, Vaubourgeix J, Burns-Huang K, Gold B. Targeting the proteostasis

network for mycobacterial drug discovery. ACS Infect Dis. 2018;4:478–98.

33. Sargeant J, Hay JC. Ca2+ regulation of constitutive vesicle trafficking. Faculty Rev

2022, 11. https://pubmed.ncbi.nlm.nih.gov/35359486/.

34. Sadasivan S, Waghray A, Larner SF, Dunn WA, Hayes RL, Wang KKW. Amino acid

starvation induced autophagic cell death in PC-12 cells: Evidence for activation of

caspase-3 but not calpain-1. Apoptosis. 2006;11:1573–82.

35. Hartl D, Kerbiriou M, Teng L, Benz N, Trouvé P, Férec C. The Calpain, Caspase 12,

Caspase 3 cascade leading to apoptosis is altered in F508del-CFTR expressing

cells. PLoS ONE. 2009;4:e8436.

36. Lee JK, Kang S, Wang X, Rosales JL, Gao X, Byun H-G, et al. HAP1 loss confers

l-asparaginase resistance in ALL by downregulating the calpain-1-Bid-caspase-3/

12 pathway. Blood. 2019;133:2222–32.

37. Zhang G, Wang X, Rothermel BA, Lavandero S, Wang ZV. The integrated stress

response in ischemic diseases. Cell Death Differ. 2021;29:750–7.

38. Ferreira M, Beullens M, Bollen M, Van Eynde A. Functions and therapeutic

potential of protein phosphatase 1: Insights from mouse genetics. Biochimica et

Biophysica Acta (BBA) - Mol Cell Res. 2019;1866:16–30.

39. Hetz C, Axten JM, Patterson JB. Pharmacological targeting of the unfolded protein response for disease intervention. Nat Cheml Biol. 2019;15:764–75.

40. Liang SH, Zhang W, McGrath BC, Zhang P, Cavener DR. PERK (eIF2α kinase) is required

to activate the stress-activated MAPKs and induce the expression of immediate-early

genes upon disruption of ER calcium homoeostasis. Biochem J. 2005;393:201–9.

41. DuRose JB, Tam AB, Niwa M. Intrinsic capacities of molecular sensors of the

unfolded protein response to sense alternate forms of endoplasmic reticulum

stress. Mol Biol Cell. 2006;17:3085–107.

42. Zhu S, McGrath BC, Bai Y, Tang X, Cavener DR. PERK regulates Gq protein-coupled

intracellular Ca2+ dynamics in primary cortical neurons. Mol Brain. 2016;9:87.

Cell Death and Disease (2023)14:848

43. Xu S, Xu Y, Chen L, Fang Q, Song S, Chen J, et al. RCN1 suppresses ER stressinduced apoptosis via calcium homeostasis and PERK–CHOP signaling. Oncogenesis. 2017;6:e304.

44. Zhang Y, Sun R, Geng S, Shan Y, Li X, Fang W. Porcine Circovirus Type 2 induces

ORF3-independent mitochondrial apoptosis via PERK activation and elevation of

cytosolic calcium. Viruses. 2019;93:e01784–01718.

45. Gautier L, Cope L, Bolstad BM, Irizarry RA. affy–analysis of Affymetrix GeneChip

data at the probe level. Bioinformatics. 2004;20:307–15.

46. Miyazaki Y, Ichimura A, Kitayama R, Okamoto N, Yasue T, Liu F, et al. C-type

natriuretic peptide facilitates autonomic Ca2+ entry in growth plate chondrocytes

for stimulating bone growth. eLife. 2022;11:e71931.

ACKNOWLEDGEMENTS

We thank Mr. Jun Matsushita (Graduate School of Pharmaceutical Sciences, Kyoto

University) for mouse in vitro fertilization. This work was supported in part by the

MEXT/JSPS (KAKENHI Grant Number 21H02663, 20H03802 and 21K19565), Platform

Project for Supporting Drug Discovery and Life Science Research

(JP19am0101092j0003), Takeda Science Foundation, Kobayashi International Scholarship Foundation, the NAKATOMI Foundation, Vehicle Racing Commemorative

Foundation, Mother and Child Health Foundation and Japan Foundation for Applied

Enzymology.

AUTHOR CONTRIBUTIONS

A.I. and Y.M. are equally contributing first authors. Y.M., H.N. and A.I. conducted Ca2+

imaging analysis. A.I., Y.M., H.N., M.T., T.K., N.N., G-E.K., N.O., S.K. and M.N. conducted

biochemical and cell physiological analysis. S.K. conducted electron microscopy

analysis. A.I., Y.M. and H.T. drafted the manuscript. H.T. oversaw this project.

ETHICS APPROVAL AND CONSENT TO PARTICIPATE

All experiments in this study were conducted with the approval of the Animal

Research Committee according to the regulations on animal experimentation at

Kyoto University.

COMPETING INTERESTS

The authors declare no competing interests.

ADDITIONAL INFORMATION

Supplementary information The online version contains supplementary material

available at https://doi.org/10.1038/s41419-023-06285-y.

Correspondence and requests for materials should be addressed to Hiroshi

Takeshima.

Reprints and permission information is available at http://www.nature.com/

reprints

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims

in published maps and institutional affiliations.

Open Access This article is licensed under a Creative Commons

Attribution 4.0 International License, which permits use, sharing,

adaptation, distribution and reproduction in any medium or format, as long as you give

appropriate credit to the original author(s) and the source, provide a link to the Creative

Commons license, and indicate if changes were made. The images or other third party

material in this article are included in the article’s Creative Commons license, unless

indicated otherwise in a credit line to the material. If material is not included in the

article’s Creative Commons license and your intended use is not permitted by statutory

regulation or exceeds the permitted use, you will need to obtain permission directly

from the copyright holder. To view a copy of this license, visit http://

creativecommons.org/licenses/by/4.0/.

© The Author(s) 2023

...