PLEKHM1/DEF8/RAB7 complex regulates lysosome positioning and bone homeostasis

Fujiwara, Toshifumi; Ye, Shiqiao; Castro-Gomes, Thiago; Winchell, Caylin G.; Andrews, Norma W.; Voth, Daniel E.; Varughese, Kottayil I.; Mackintosh, Samuel G.; Feng, Yunfeng; Pavlos, Nathan J.; Nakamura, Takashi; Manolagas, Stavros C.; Zhao, Haibo

doi:10.1172/jci.insight.86330

Cited by 74 publications

(77 citation statements)

References 85 publications

(102 reference statements)

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“…This may reflect the fact that not all Rab7 effectors are equally regulated by PI(4,5)P 2 in late endosomes. Curiously, we found no obvious difference in lysosome distribution in our PI4K2A K/O cells even though Rab7 and PLEKHM1 were found important in lysosomal positioning (Mrakovic et al , ; Fujiwara et al , ; Willett et al , ). Several other trafficking steps that involve Rab7 GTPases were shown previously to be controlled by PI4P.…”

Section: Discussionmentioning

confidence: 58%

Phosphatidylinositol 4,5‐bisphosphate controls Rab7 and PLEKHM 1 membrane cycling during autophagosome–lysosome fusion

et al. 2019

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The small GTPase Rab7 is a key organizer of receptor sorting and lysosomal degradation by recruiting of a variety of effectors depending on its GDP/GTP‐bound state. However, molecular mechanisms that trigger Rab7 inactivation remain elusive. Here we find that, among the endosomal pools, Rab7‐positive compartments possess the highest level of PI4P, which is primarily produced by PI4K2A kinase. Acute conversion of this endosomal PI4P to PI(4,5)P2 causes Rab7 dissociation from late endosomes and releases a regulator of autophagosome–lysosome fusion, PLEKHM1, from the membrane. Rab7 effectors Vps35 and RILP are not affected by acute PI(4,5)P2 production. Deletion of PI4K2A greatly reduces PIP5Kγ‐mediated PI(4,5)P2 production in Rab7‐positive endosomes leading to impaired Rab7 inactivation and increased number of LC3‐positive structures with defective autophagosome–lysosome fusion. These results reveal a late endosomal PI4P‐PI(4,5)P2‐dependent regulatory loop that impacts autophagosome flux by affecting Rab7 cycling and PLEKHM1 association.

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Section: Discussionmentioning

confidence: 58%

Phosphatidylinositol 4,5‐bisphosphate controls Rab7 and PLEKHM 1 membrane cycling during autophagosome–lysosome fusion

et al. 2019

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“…Bone homeostasis is maintained by the balance between osteoblast-mediated bone formation and osteoclast-mediated bone resorption. 13,14 In the present study, we investigated the role of GDF8 in bone formation in vitro and in vivo, and showed that GDF8 inhibited mouse osteoblast differentiation and repressed bone formation in vivo. Accumulated data demonstrate that GDF8 plays an inhibitory role in controlling bone mass.…”

Section: Discussionmentioning

confidence: 85%

GDF8 inhibits bone formation and promotes bone resorption in mice

Chen

Guo

et al. 2017

Clin Exp Pharma Physio

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Growth Differentiation Factor 8 (GDF8), also called myostatin, is a member of the transforming growth factor (TGF)-β super-family. As a negative regulator of skeletal muscle growth, GDF8 is also associated with bone metabolism. However, the function of GDF8 in bone metabolism is not fully understood. Our study aimed to investigate the role of GDF8 in bone metabolism, both in vitro and in vivo. Our results showed that GDF8 had a negative regulatory effect on primary mouse osteoblasts, and promoted receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclastogenesis in vitro. Intraperitoneal injection of recombinant GDF8 repressed bone formation and accelerated bone resorption in mice. Furthermore, treatment of aged mice with a GDF8 neutralizing antibody stimulated new bone formation and prevented bone resorption. Thus, our study showed that GDF8 plays a significant regulatory role in bone formation and bone resorption, thus providing a potential therapeutic pathway for osteoporosis.

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“…Mature osteoclasts grown on bone slices were removed with a soft brush, and resorption pits were stained as described previously (87). In brief, bone slices were incubated with 20 g/ml peroxidase-conjugated wheat germ agglutinin (WGA) lectin (catalogue no.…”

Section: Tracp Staining and Resorption Pit Stainingmentioning

confidence: 99%

Deletion of ferroportin in murine myeloid cells increases iron accumulation and stimulates osteoclastogenesis in vitro and in vivo

Wang

Fang

Fujiwara³

et al. 2018

Journal of Biological Chemistry

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Osteoporosis, osteopenia, and pathological bone fractures are frequent complications of iron-overload conditions such as hereditary hemochromatosis, thalassemia, and sickle cell disease. Moreover, animal models of iron overload have revealed increased bone resorption and decreased bone formation. Although systemic iron overload affects multiple organs and tissues, leading to significant changes on bone modeling and remodeling, the cell autonomous effects of excessive iron on bone cells remain unknown. Here, to elucidate the role of cellular iron homeostasis in osteoclasts, we generated two mouse strains in which solute carrier family 40 member 1 (), a gene encoding ferroportin (FPN), the sole iron exporter in mammalian cells, was specifically deleted in myeloid osteoclast precursors or mature cells. The FPN deletion mildly increased iron levels in both precursor and mature osteoclasts, and its loss in precursors, but not in mature cells, increased osteoclastogenesis and decreased bone mass Of note, these phenotypes were more pronounced in female than in male mice. studies revealed that the elevated intracellular iron promoted macrophage proliferation and amplified expression of nuclear factor of activated T cells 1 (Nfatc1) and PPARG coactivator 1β (Pgc-1β), two transcription factors critical for osteoclast differentiation. However, the iron excess did not affect osteoclast survival. While increased iron stimulated global mitochondrial metabolism in osteoclast precursors, it had little influence on mitochondrial mass and reactive oxygen species production. These results indicate that FPN-regulated intracellular iron levels are critical for mitochondrial metabolism, osteoclastogenesis, and skeletal homeostasis in mice.

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PLEKHM1/DEF8/RAB7 complex regulates lysosome positioning and bone homeostasis

Cited by 74 publications

References 85 publications

Phosphatidylinositol 4,5‐bisphosphate controls Rab7 and PLEKHM 1 membrane cycling during autophagosome–lysosome fusion

Phosphatidylinositol 4,5‐bisphosphate controls Rab7 and PLEKHM 1 membrane cycling during autophagosome–lysosome fusion

GDF8 inhibits bone formation and promotes bone resorption in mice

Deletion of ferroportin in murine myeloid cells increases iron accumulation and stimulates osteoclastogenesis in vitro and in vivo

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