The unfolded protein response mediates fibrogenesis and collagen I secretion through regulating TANGO1 in mice

Jessica Maiers, Enis Kostallari, Malek Mushref, Thiago M. deAssuncao, Haiyang Li, Nidhi Jalan-Sakrikar, Robert C Huebert, Sheng Cao, Harmeet M Malhi, Vijay Shah

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

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. Conclusion: Loss 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 2016).

Original languageEnglish (US)
JournalHepatology
DOIs
StateAccepted/In press - 2016

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Unfolded Protein Response
Hepatic Stellate Cells
Collagen
Procollagen
Endoplasmic Reticulum
Factor X
Transforming Growth Factors
Apoptosis
Fibrosis
Transcription Factors
Proteins
Secretory Pathway
Liver
Gastroenterology
Bile Ducts
Small Interfering RNA
Extracellular Matrix
Ligation
Homeostasis
Up-Regulation

ASJC Scopus subject areas

  • Hepatology

Cite this

The unfolded protein response mediates fibrogenesis and collagen I secretion through regulating TANGO1 in mice. / Maiers, Jessica; Kostallari, Enis; Mushref, Malek; deAssuncao, Thiago M.; Li, Haiyang; Jalan-Sakrikar, Nidhi; Huebert, Robert C; Cao, Sheng; Malhi, Harmeet M; Shah, Vijay.

In: Hepatology, 2016.

Research output: Contribution to journalArticle

Maiers, Jessica ; Kostallari, Enis ; Mushref, Malek ; deAssuncao, Thiago M. ; Li, Haiyang ; Jalan-Sakrikar, Nidhi ; Huebert, Robert C ; Cao, Sheng ; Malhi, Harmeet M ; Shah, Vijay. / The unfolded protein response mediates fibrogenesis and collagen I secretion through regulating TANGO1 in mice. In: Hepatology. 2016.
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abstract = "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. Conclusion: Loss 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 2016).",
author = "Jessica Maiers and Enis Kostallari and Malek Mushref and deAssuncao, {Thiago M.} and Haiyang Li and Nidhi Jalan-Sakrikar and Huebert, {Robert C} and Sheng Cao and Malhi, {Harmeet M} and Vijay Shah",
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T1 - The unfolded protein response mediates fibrogenesis and collagen I secretion through regulating TANGO1 in mice

AU - Maiers, Jessica

AU - Kostallari, Enis

AU - Mushref, Malek

AU - deAssuncao, Thiago M.

AU - Li, Haiyang

AU - Jalan-Sakrikar, Nidhi

AU - Huebert, Robert C

AU - Cao, Sheng

AU - Malhi, Harmeet M

AU - Shah, Vijay

PY - 2016

Y1 - 2016

N2 - 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. Conclusion: Loss 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 2016).

AB - 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. Conclusion: Loss 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 2016).

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