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

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Abstract

Secretion and quality control of large extracellular matrix proteins remain poorly understood and debated, particularly transport intermediates delivering folded proteins from the ER to Golgi and misfolded ones to lysosomes. Discrepancies between different studies are related to utilization of exogenous cargo, off-target effects of experimental conditions and cell manipulation, and identification of transport intermediates without tracing their origin and destination. To address these issues, here we imaged secretory and degradative trafficking of type I procollagen in live MC3T3 osteoblasts by replacing a region encoding N-propeptide in endogenous Col1a2 gDNA with GFP cDNA. We selected clones that produced the resulting fluorescent procollagen yet had normal expression of key osteoblast and ER/cell stress genes, normal procollagen folding, and normal deposition and mineralization of extracellular matrix. Live-cell imaging of these clones revealed ARF1-dependent transport intermediates, which had no COPII coat and delivered procollagen from ER exit sites (ERESs) to Golgi without stopping at ER–Golgi intermediate compartment (ERGIC). It also confirmed ERES microautophagy, i.e., lysosomes engulfing ERESs containing misfolded procollagen. Beyond validating these trafficking models for endogenous procollagen, we uncovered a probable cause of noncanonical cell stress response to procollagen misfolding. Recognized and retained only at ERESs, misfolded procollagen does not directly activate the canonical UPR, yet it disrupts the ER lumen by blocking normal secretory export from the ER.

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All cell lines, plasmids, and data generated in this study will be deposited to public repositories or freely provided upon request after acceptance of the paper for publication.

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Acknowledgements

This work was funded by the Intramural Research Program of NICHD, NIH. The authors thank Juan Bonifacino (NICHD) and Jennifer Lippincott-Schwartz (Howard Hughes Medical Institute, Janelia Research Campus) for access to super-resolution microscopes in their laboratories. They also thank Vincent Schram for assistance in imaging at NICHD Microscopy and Imaging Core.

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This work was funded by the Intramural Research Program of NICHD, NIH.

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  1. Shakib Omari

    Present address: Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA

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  1. Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, MD, 20892, USA

    Laura Gorrell, Shakib Omari, Elena Makareeva & Sergey Leikin

  2. Rensselaer Polytechnic Institute, Troy, NY, 12180, USA

    Laura Gorrell

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LG, SO, EM, and SL contributed to Study design; LG, SO, and EM performed experiments; LG, SO, EM, and SL performed data analysis; LG, SO, EM, and SL were involved in writing and revising the paper.

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Correspondence to Sergey Leikin.

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Gorrell, L., Omari, S., Makareeva, E. et al. Noncanonical ER–Golgi trafficking and autophagy of endogenous procollagen in osteoblasts. Cell. Mol. Life Sci. 78, 8283–8300 (2021). https://doi.org/10.1007/s00018-021-04017-z

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