Intracellular trafficking and degradation of unassociated proα2 chains of collagen type I

GOTKIN, M; Ripley, Catherine R.; Lamandé, Shireen R.; Bateman, John F.; Bienkowski, Robert S.

doi:10.1016/j.yexcr.2004.01.029

Cited by 17 publications

(14 citation statements)

References 51 publications

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“…Type I collagen is a trimer of two ␣1 chains and one ␣2 chain. In Mov13 cells, which lacks collagen pro␣1(I) chain expression (Schnieke et al, 1983;Breindl et al, 1984), the pro␣2(I) chain is rapidly degraded by the lysosome (Gotkin et al, 2004), which was confirmed in the present study. By reintroducing normal or mutant pro␣1(I) chains into Mov13 cells, the assembly (trimer formation) and triple helix formation of the ␣ chains can be analyzed.…”

Section: Discussionsupporting

confidence: 88%

“…We first examined pro␣2(I) chain degradation in Mov13 cells and found that it is degraded via the lysosomal pathway, as indicated by the effect of lysosomal inhibitors ( Figure 6A). Proteasome inhibitors did not inhibit pro␣2(I) chain degradation in Mov13 cells, consistent with a previous report (Gotkin et al, 2004). Because this degradation was inhibited by the treatment of cells with brefeldin A, pro␣2(I) chain in Mov13 cells is assumed to be degraded via COPII pathway.…”

Section: Autophagy-dependent Degradation Of Disease-causing Mutants Osupporting

confidence: 90%

“…Intriguingly, the pro␣2(I) chain in Mov13 cells is not degraded through ERAD or autophagy, but by lysosomes via an autophagy-independent pathway (Figure 6). The pro␣2(I) chain in Mov13 cells is transported to the Golgi apparatus before being degraded in the lysosome (Gotkin et al, 2004), which may suggest the existence of additional components responsible for discriminating misfolded procollagens. However, detailed mechanisms for the third degradation pathway remain to be investigated.…”

Section: Discussionmentioning

confidence: 99%

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Autophagic Elimination of Misfolded Procollagen Aggregates in the Endoplasmic Reticulum as a Means of Cell Protection

Ishida

Yamamoto

Kitamura

et al. 2009

MBoC

190

199

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Type I collagen is a major component of the extracellular matrix, and mutations in the collagen gene cause several matrix-associated diseases. These mutant procollagens are misfolded and often aggregated in the endoplasmic reticulum (ER). Although the misfolded procollagens are potentially toxic to the cell, little is known about how they are eliminated from the ER. Here, we show that procollagen that can initially trimerize but then aggregates in the ER are eliminated by an autophagy-lysosome pathway, but not by the ER-associated degradation (ERAD) pathway. Inhibition of autophagy by specific inhibitors or RNAi-mediated knockdown of an autophagy-related gene significantly stimulated accumulation of aggregated procollagen trimers in the ER, and activation of autophagy with rapamycin resulted in reduced amount of aggregates. In contrast, a mutant procollagen which has a compromised ability to form trimers was degraded by ERAD. Moreover, we found that autophagy plays an essential role in protecting cells against the toxicity of the ERAD-inefficient procollagen aggregates. The autophagic elimination of aggregated procollagen occurs independently of the ERAD system. These results indicate that autophagy is a final cell protection strategy deployed against ER-accumulated cytotoxic aggregates that are not able to be removed by ERAD.

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Section: Discussionsupporting

confidence: 88%

Section: Autophagy-dependent Degradation Of Disease-causing Mutants Osupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Autophagic Elimination of Misfolded Procollagen Aggregates in the Endoplasmic Reticulum as a Means of Cell Protection

Ishida

Yamamoto

Kitamura

et al. 2009

MBoC

190

199

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“…Furthermore, pVHL does not appear to interact with native extracellular (triple helical) collagen but with unassembled intracellular collagen IV chains. Several different intracellular routes of degradation for unassembled collagen chains have been described, including proteasomal degradation (24,25). However, despite the established function in degradation of HIF-␣, we have so far been unable to demonstrate similar pVHL-dependent processing of collagen IV chains.…”

Section: Discussionmentioning

confidence: 62%

Interaction of Hydroxylated Collagen IV with the von Hippel-Lindau Tumor Suppressor

Grosfeld

Stolze

Cockman

et al. 2007

Journal of Biological Chemistry

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The von Hippel-Lindau tumor suppressor (pVHL) targets hydroxylated ␣-subunits of hypoxia-inducible factor (HIF) for ubiquitin-mediated proteasomal destruction through direct interaction with the hydroxyproline binding pocket in its ␤-domain. Although disruption of this process may contribute to VHL-associated tumor predisposition by up-regulation of HIF target genes, genetic and biochemical analyses support the existence of additional functions, including a role in the assembly of extracellular matrix. In an attempt to delineate these pathways, we searched for novel pVHL-binding proteins. Here we report a direct, hydroxylation-dependent interaction with ␣-chains of collagen IV. Interaction with pVHL was also observed with fibrillar collagen chains, but not the folded collagen triple helix. The interaction was suppressed by a wide range of tumor-associated mutations, including those that do not disturb the regulation of HIF, supporting a role in HIF-independent tumor suppressor functions.

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“…In these cells, unfolded pro-α2(I) procollagen chains (which do not fold without pro-α1(I)) are transported from ER to Golgi and seem to be targeted for degradation in lysosomes via an unknown pathway [63]. …”

Section: When Chaperones Fail: Unfolded Protein Responsementioning

confidence: 99%

Chaperoning osteogenesis: new protein-folding disease paradigms

Makareeva

Aviles

Leikin

2011

Trends in Cell Biology

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Recent discoveries of severe bone disorders in patients with deficiencies in several endoplasmic reticulum chaperones are reshaping the discussion of type I collagen folding and related diseases. Type I collagen is the most abundant protein in all vertebrates and a crucial structural molecule for bone and other connective tissues. Its misfolding causes bone fragility, skeletal deformities and other tissue failures. Studies of newly discovered bone disorders indicate that collagen folding, chaperones involved in the folding process, cellular responses to misfolding, and related bone pathologies may not follow conventional protein folding paradigms. In this review, we examine the features that distinguish collagen folding from that of other proteins and describe findings that are beginning to reveal how cells manage collagen folding and misfolding. We discuss implications of these studies on general protein folding paradigms, unfolded protein response in cells and protein folding diseases. Sans chaperones: osteogenesis choreography gone astrayBone consists of flexible type I collagen fibers and hard hydroxyappatite mineral, making bone material strong yet not brittle. Bone formation (osteogenesis) involves an intricate choreography of specialized cells (Figure 1). Osteoblasts deposit collagen fibers and promote mineralization, osteoclasts resorb older bone and osteocytes act as mechano-sensors that are embedded in bone. These cells interact with each other and are regulated by outside signals from cytokines, hormones and the sympathetic nervous system [1][2][3]. Osteogenesis disorders may be caused by bone cell malfunctions and defects in the collagen matrix.Endoplasmic reticulum (ER) chaperones were brought to the forefront of osteogenesis research by recent discoveries of several new forms of osteogenesis imperfecta (OI). OI is a group of hereditary disorders characterized by bone fractures and deformities [4,5]. Deficiencies in five ER chaperones --CRTAP, P3H1, CYPB, FKBP65, and HSP47 --were found to cause severe OI by leading astray type I collagen folding and osteogenesis choreography [6][7][8][9][10][11][12][13][14][15][16]. The apparent roles of these chaperones in disease pathology, however, presented an unexpected puzzle.Most chaperones assist protein folding by protecting unfolded chains from nonspecific interactions and by catalyzing peptide and disulfide bond isomerization [17][18][19]. However, the functions of CRTAP, P3H1, CYPB, FKBP65, and HSP47 in collagen folding do not Corresponding author: Leikin, S. (leikins@mail.nih.gov).

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Intracellular trafficking and degradation of unassociated proα2 chains of collagen type I

Cited by 17 publications

References 51 publications

Autophagic Elimination of Misfolded Procollagen Aggregates in the Endoplasmic Reticulum as a Means of Cell Protection

Autophagic Elimination of Misfolded Procollagen Aggregates in the Endoplasmic Reticulum as a Means of Cell Protection

Interaction of Hydroxylated Collagen IV with the von Hippel-Lindau Tumor Suppressor

Chaperoning osteogenesis: new protein-folding disease paradigms

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