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Distinct isoform-specific complexes of TANGO1 cooperatively facilitate collagen secretion from the endoplasmic reticulum.

ABSTRACT: Collagens synthesized within the endoplasmic reticulum (ER) are too large to fit in conventional COPII-coated transport vesicles; thus their export from the ER requires specialized factors. TANGO1 (L) is an integral membrane protein that binds to collagen and the coatomer of vesicles and is necessary for collagen secretion from the ER. Here we characterized the short isoform of TANGO1 (TANGO1S), lacking the collagen-binding domain, and found that it was independently required for collagen export from the ER. Moreover, we found that each of the TANGO1 isoforms forms a stable protein complex with factors involved in collagen secretion: TANGO1L/cTAGE5/Sec12 (900 kDa) and TANGO1S/cTAGE5/Sec12 (700 kDa). Of interest, TANGO1S and TANGO1L seemed to be interchangeable in exporting collagen from the ER. Our results suggest that mammalian ER exit sites possess two different-sized membrane-bound macromolecular complexes that specifically function in large-cargo export from the ER.

SUBMITTER: Maeda M

PROVIDER: S-EPMC5007089 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Distinct isoform-specific complexes of TANGO1 cooperatively facilitate collagen secretion from the endoplasmic reticulum.

Maeda Miharu M Saito Kota K Katada Toshiaki T

Molecular biology of the cell 20160713 17

Collagens synthesized within the endoplasmic reticulum (ER) are too large to fit in conventional COPII-coated transport vesicles; thus their export from the ER requires specialized factors. TANGO1 (L) is an integral membrane protein that binds to collagen and the coatomer of vesicles and is necessary for collagen secretion from the ER. Here we characterized the short isoform of TANGO1 (TANGO1S), lacking the collagen-binding domain, and found that it was independently required for collagen export ...[more]

PMID: 27413011

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Project description:Fibrogenesis encompasses the deposition of matrix proteins, such as collagen I, by hepatic stellate cells (HSCs) that culminates in cirrhosis. Fibrogenic signals drive transcription of procollagen I, which enters the endoplasmic reticulum (ER), is trafficked through the secretory pathway, and released to generate extracellular matrix. Alternatively, disruption of procollagen I ER export could activate the unfolded protein response (UPR) and drive HSC apoptosis. Using a small interfering RNA screen, we identified Transport and Golgi organization 1 (TANGO1) as a potential participant in collagen I secretion. We investigated the role of TANGO1 in procollagen I secretion in HSCs and liver fibrogenesis. Depletion of TANGO1 in HSCs blocked collagen I secretion without affecting other matrix proteins. Disruption of secretion led to procollagen I retention within the ER, induction of the UPR, and HSC apoptosis. In wild-type (WT) HSCs, both TANGO1 and the UPR were induced by transforming growth factor β (TGFβ). As the UPR up-regulates proteins involved in secretion, we studied whether TANGO1 was a target of the UPR. We found that UPR signaling is responsible for up-regulating TANGO1 in response to TGFβ, and this mechanism is mediated by the transcription factor X-box binding protein 1 (XBP1). In vivo, murine and human cirrhotic tissue displayed increased TANGO1 messenger RNA levels. Finally, TANGO1+/- mice displayed less hepatic fibrosis compared to WT mice in two separate murine models: CCl4 and bile duct ligation.ConclusionLoss of TANGO1 leads to procollagen I retention in the ER, which promotes UPR-mediated HSC apoptosis. TANGO1 regulation during HSC activation occurs through a UPR-dependent mechanism that requires the transcription factor, XBP1. Finally, TANGO1 is critical for fibrogenesis through mediating HSC homeostasis. The work reveals a unique role for TANGO1 and the UPR in facilitating collagen I secretion and fibrogenesis. (Hepatology 2017;65:983-998).

Project description:Flaviviruses, including dengue virus (DENV) and Zika virus (ZIKV), rely heavily on the availability of endoplasmic reticulum (ER) membranes throughout their life cycle, and degradation of ER membranes restricts flavivirus replication. Accordingly, DENV and ZIKV restrict ER turnover by protease-mediated cleavage of reticulophagy regulator 1 (RETREG1), also known as FAM134B, an autophagy receptor responsible for targeted ER sheet degradation. Given that the induction of autophagy may play an important role in flavivirus replication, the antiviral role of RETREG1 suggests that specialized autophagic pathways may have differential effects on the flavivirus life cycle. We previously identified BPI fold-containing family B member 3 (BPIFB3) as a regulator of autophagy that negatively controls enterovirus replication. Here, we show that in contrast to enteroviruses, BPIFB3 functions as a positive regulator of DENV and ZIKV infection and that its RNA interference-mediated silencing inhibits the formation of viral replication organelles. Mechanistically, we show that depletion of BPIFB3 enhances RETREG1-dependent reticulophagy, leading to enhanced ER turnover and the suppression of viral replication. Consistent with this, the antiviral effects of BPIFB3 depletion can be reversed by RETREG1 silencing, suggesting a specific role for BPIFB3 in regulating ER turnover. These studies define BPIFB3 as a required host factor for both DENV and ZIKV replication and further contribute to our understanding of the requirements for autophagy during flavivirus infection.IMPORTANCE Flaviviruses and other arthropod-transmitted viruses represent a widespread global health problem, with limited treatment options currently available. Thus, a better understanding of the cellular requirements for their infection is needed. Both DENV and ZIKV rely on expansion of the endoplasmic reticulum (ER) and the induction of autophagy to establish productive infections. However, little is known regarding the interplay between the requirements for autophagy initiation during infection and the mechanisms used by these viruses to avoid clearance through the autophagic pathway. Our study highlights the importance of the host factor BPIFB3 in regulating flavivirus replication and further confirms that the RETREG1-dependent reticulophagy pathway is antiviral to both DENV and ZIKV.

Dataset Information

Distinct isoform-specific complexes of TANGO1 cooperatively facilitate collagen secretion from the endoplasmic reticulum.

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Distinct isoform-specific complexes of TANGO1 cooperatively facilitate collagen secretion from the endoplasmic reticulum.

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