Noncanonical ER–Golgi trafficking and autophagy of endogenous procollagen in osteoblasts

Gorrell, Laura; Omari, Shakib; Makareeva, Elena; Leikin, Sergey

doi:10.1007/s00018-021-04017-z

Cited by 14 publications

(20 citation statements)

References 64 publications

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“…On its own, collagen triple helix misfolding does not sequester the master regulator of UPR, BIP ( 45 ), explaining why it does not trigger UPR in osteoblasts ( 17 ). However, the resulting ER disruption ( Figure 6 ) could result in misfolding of globular proteins, causing BIP sequestration and UPR as a secondary response in HCs ( 72 ). For instance, ER disruption by the mutation in HCs could affect folding of type II, IX, X, and XI collagen; martrilin-3; cartilage oligomeric matrix protein (COMP); and other matrix proteins known to cause cell stress in chondrocytes in various cartilage disorders ( 40 , 43 , 44 , 73 , 74 ).…”

Section: Discussionmentioning

confidence: 99%

4PBA reduces growth deficiency in osteogenesis imperfecta by enhancing transition of hypertrophic chondrocytes to osteoblasts

Scheiber¹,

Wilkinson²,

Suzuki³

et al. 2022

JCI Insight

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Short stature is a major skeletal phenotype in osteogenesis imperfecta (OI), a genetic disorder mainly caused by mutations in genes encoding type I collagen. However, the underlying mechanism is poorly understood and no effective treatment is available. In OI mice that carry a G610C mutation in COL1A2, we previously found that mature hypertrophic chondrocytes (HCs) are exposed to cell stress due to accumulation of misfolded mutant type I procollagen in the endoplasmic reticulum (ER). By fate mapping analysis of HCs in G610C OI mice, we found that HCs stagnate in the growth plate, inhibiting translocation of HC descendants to the trabecular area and their differentiation to osteoblasts. Treatment with 4-phenylbutyric acid (4PBA), a chemical chaperone, restored HC ER structure and rescued this inhibition, resulting in enhanced longitudinal bone growth in G610C OI mice. Interestingly, the effects of 4PBA on ER dilation were limited in osteoblasts and the bone fragility was not ameliorated. These results highlight the importance of targeting HCs to treat growth deficiency in OI. Our findings demonstrate that HC dysfunction induced by ER disruption plays a critical role in the pathogenesis of OI growth deficiency, which lays the foundation for developing new therapies for OI.

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Section: Discussionmentioning

confidence: 99%

4PBA reduces growth deficiency in osteogenesis imperfecta by enhancing transition of hypertrophic chondrocytes to osteoblasts

Scheiber¹,

Wilkinson²,

Suzuki³

et al. 2022

JCI Insight

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“…This interpretation of the data is consistent with equally efficient secretion of molecules with and without the mutant pro α 2(I) chain. [ 13,25b,c ] Mutant and normal procollagen enter ER exit sites (ERESs) together, where misfolded procollagen aggregates tend to prevent formation of ER‐Golgi transport intermediates and initiate ERES degradation by lysosomes. [ 25a,c ] The resulting blockage and depletion of functional ERESs needed for protein export from the ER causes procollagen accumulation in the ER lumen, dilation of the lumen, and therefore ER disruption.…”

Section: Discussionmentioning

confidence: 99%

“…[ 13,25b,c ] Mutant and normal procollagen enter ER exit sites (ERESs) together, where misfolded procollagen aggregates tend to prevent formation of ER‐Golgi transport intermediates and initiate ERES degradation by lysosomes. [ 25a,c ] The resulting blockage and depletion of functional ERESs needed for protein export from the ER causes procollagen accumulation in the ER lumen, dilation of the lumen, and therefore ER disruption. [ 25 ] However, the ER lumen does not seem to have receptors recognizing this disruption.…”

Section: Discussionmentioning

confidence: 99%

ER, Mitochondria, and ISR Regulation by mt‐HSP70 and ATF5 upon Procollagen Misfolding in Osteoblasts

et al. 2022

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Cellular response to protein misfolding underlies multiple diseases. Collagens are the most abundant vertebrate proteins, yet little is known about cellular response to misfolding of their procollagen precursors. Osteoblasts (OBs)—the cells that make bone—produce so much procollagen that it accounts for up to 40% of mRNAs in the cell, which is why bone bears the brunt of mutations causing procollagen misfolding in osteogenesis imperfecta (OI). The present study of a G610C mouse model of OI by multiple transcriptomic techniques provides first solid clues to how OBs respond to misfolded procollagen accumulation in the endoplasmic reticulum (ER) and how this response affects OB function. Surprisingly, misfolded procollagen escapes the quality control in the ER lumen and indirectly triggers the integrated stress response (ISR) through other cell compartments. In G610C OBs, the ISR is regulated by mitochondrial HSP70 (mt‐HSP70) and ATF5 instead of their BIP and ATF4 paralogues, which normally activate and regulate ISR to secretory protein misfolding in the ER. The involvement of mt‐HSP70 and ATF5 together with other transcriptomic findings suggest that mitochondria might initiate the ISR upon disruption of ER‐mitochondria connections or might respond to the ISR activated by a yet unknown sensor.

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“…In contrast, the engagement of the FAM134-CNX complexes by mutant forms of pro-collagen triggers the formation of ER-derived fragments that are captured by nascent autophagosomes ( FIGURE 19 , Macro-ER-phagy) ( 198 , 207 ). Notably, autophagosomes are dispensable for the clearance of ER portions containing other forms of misfolded pro-collagen, e.g., the G610C mutant, which is segregated in osteoblasts’ and osteoclasts’ ER exit sites and turned over by micro-ER-phagy ( FIGURE 19 , Micro-ER-phagy) ( 326 , 329 , 330 ).…”

Section: Autophagy Of the Er: Er-phagymentioning

confidence: 99%

ER-phagy: mechanisms, regulation, and diseases connected to the lysosomal clearance of the endoplasmic reticulum

Reggiori

Molinari

2022

Physiological Reviews

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ER-phagy (reticulo-phagy) defines the degradation of portions of the endoplasmic reticulum (ER) within lysosomes or vacuoles. It is part of the self-digestion (i.e., auto-phagic) programs recycling cytoplasmic material and organelles, which rapidly mobilize metabolites in cells confronted with nutrient shortage. Moreover, selective clearance of ER subdomains participates to the control of ER size and activity during ER stress, the re-establishment of ER homeostasis after ER stress resolution and the removal of ER parts, in which aberrant and potentially cytotoxic material has been segregated. ER-phagy relies on the individual and/or concerted activation of the ER-phagy receptors, ER peripheral or integral membrane proteins that share the presence of LC3/Atg8-binding motifs in their cytosolic domains. ER-phagy involves the physical separation of portions of the ER from the bulk ER network, and their delivery to the endolysosomal/vacuolar catabolic district. This last step is accomplished by a variety of mechanisms including macro-ER-phagy (in which ER fragments are sequestered by double-membrane autophagosomes that eventually fuse with lysosomes/vacuoles), micro-ER-phagy (in which ER fragments are directly engulfed by endosomes/lysosomes/vacuoles), or direct fusion of ER-derived vesicles with lysosomes/vacuoles. ER-phagy is dysfunctional in specific human diseases and its regulators are subverted by pathogens, highlighting its crucial role for cell and organism life.

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Noncanonical ER–Golgi trafficking and autophagy of endogenous procollagen in osteoblasts

Cited by 14 publications

References 64 publications

4PBA reduces growth deficiency in osteogenesis imperfecta by enhancing transition of hypertrophic chondrocytes to osteoblasts

4PBA reduces growth deficiency in osteogenesis imperfecta by enhancing transition of hypertrophic chondrocytes to osteoblasts

ER, Mitochondria, and ISR Regulation by mt‐HSP70 and ATF5 upon Procollagen Misfolding in Osteoblasts

ER-phagy: mechanisms, regulation, and diseases connected to the lysosomal clearance of the endoplasmic reticulum

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