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Collagen secretion explained

Nature volume 482, pages 474475 (23 February 2012) | Download Citation

Cells package proteins into vesicles for secretion to the extracellular milieu. A study has now identified an enzyme that modifies the packaging machinery to encapsulate unusually large proteins, such as collagen. See Article p.495

Together with other extracellular proteins, collagen provides the structural framework on which tissues develop and function. It is synthesized in the endoplasmic reticulum, an intracellular organelle, as a rigid, rod-like precursor (procollagen) about 300 nanometres in length. Procollagen — like nearly all secreted proteins — is then packaged into transport vesicles for delivery to another organelle, the Golgi apparatus, before its secretion to the cell's surroundings. Transport vesicles, however, are typically smaller than 100 nm, as they are generated from the endoplasmic reticulum by a group of proteins (the COPII coat) that co-assemble as a structurally defined polyhedral cage1. On page 495 of this issue, Jin et al.2 reveal that modification of one of the COPII proteins allows the formation of vesicles that are large enough to hold procollagen.

The outer layer of the COPII coat is assembled using structural elements comprised of the proteins SEC13 and SEC31 (Fig. 1a). Although it was thought that the hinges between these elements are flexible enough to allow vesicles of various sizes to form3,4, little was known about how vesicle size is controlled. Jin and colleagues2 show that SEC31 can be modified by ubiquitination — the attachment of one or more copies of a small protein called ubiquitin. Although ubiquitination can 'mark' a protein for degradation, it is becoming increasingly clear that it can also affect protein function5.

Figure 1: Big vesicles for collagen secretion.
Figure 1

Soluble proteins targeted for secretion, together with small transmembrane proteins, are packaged at the endoplasmic reticulum into vesicles that are coated by the COPII protein cage. Proteins that will form the inner layer of the COPII coat associate in an ordered fashion and then recruit the proteins SEC13 and SEC31, which form the outer layer. This leads to membrane deformation and ultimately to scission of 60–80-nm transport vesicles. b, Large proteins such as procollagen (the collagen precursor) do not fit into these typical vesicles. Jin et al.2 report that, to encapsulate such large cargoes, the enzyme CUL3–KLHL12 attaches one copy of the small protein ubiquitin to SEC31 within the SEC13–SEC31 complex, and that this process facilitates collagen export. An additional, unknown protein might further stabilize lateral SEC13–SEC31 interactions. Although it is not known whether collagen synthesis directly triggers CUL3–KLHL12 activity, the transmembrane protein TANGO1 — which couples collagen in the endoplasmic reticulum to the assembling coat on the cytosolic face — might have a role in the process.

Specifically, the authors2 report that, in mouse cells, the enzyme CUL3–KLHL12 adds a single ubiquitin to a small pool of SEC31 molecules, and that this modification is required to drive the secretion of collagen. Using high-resolution electron microscopy, they found that overexpression of CUL3–KLHL12 leads to the production of large COPII structures, up to 500 nm in diameter — sufficient to accommodate procollagen. The simplest explanation for these observations is that ubiquitin attachment to SEC31 results in a structural change in the COPII cage that alters coat flexibility, and allows procollagen to be encapsulated in a nascent vesicle (Fig. 1b).

Jin and colleagues' observation that only some SEC31 molecules are modified indicates strongly that the addition of ubiquitin does not directly modulate the mechanics of COPII coat assembly. Instead, SEC31 ubiquitination might lead to recruitment of an additional, unknown protein to perform this role — for example, by further stabilizing lateral SEC13–SEC31 interactions. Identification of the additional factor and a more detailed molecular explanation of the modified geometry of the vesicle coat are challenges for the future.

Ubiquitination of some SEC31 molecules could be an ongoing process that facilitates the formation of large COPII vesicles as a routine cell function; alternatively, large vesicles might be formed only on demand. In the latter case, however, it is not immediately obvious how CUL3–KLHL12, located in the cytoplasm, would sense the presence of newly synthesized procollagen in the endoplasmic reticulum. A potential candidate for relaying this information across the endoplasmic reticulum membrane is the transmembrane protein TANGO1, which forms part of a packaging receptor that is essential for procollagen secretion6,7. TANGO1, however, does not make contact with SEC31 directly, nor is it found in fully formed vesicles, and so its possible connection to CUL3–KLHL12 is unclear.

Other questions remain. Does collagen become entirely encapsulated in a large COPII cage during vesicle formation (Fig. 1b), or does COPII somehow aid collagen export indirectly, without the need for a complete cage? And how does the addition of ubiquitin change the geometry of the COPII coat? Jin and colleagues' findings2 might aid the development of a cell-free system for studying COPII-dependent packaging of collagen that would help to address these issues. Moreover, is SEC31 ubiquitination relevant to the packaging of other large secreted macromolecules, such as lipoproteins?

These questions are relevant to our understanding not only of the fundamental mechanisms of cellular secretion, but also of diseases in which secretion (particularly of collagen) is defective because of gene mutation8. Furthermore, manipulation of the CUL3–KLHL12 ubiquitination pathway might be used to increase collagen secretion from cells for applications in stem-cell culture, for growth of tissue components in regenerative medicine, or perhaps for ameliorating age-related degeneration of connective tissue.

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  1. David J. Stephens is in the Cell Biology Laboratories, School of Biochemistry, University of Bristol, Bristol BS8 1TD, UK

    • David J. Stephens

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Correspondence to David J. Stephens.

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