# Regulation of Hepatic Fibrogeneiss by TANGO1

> **NIH NIH K01** · MAYO CLINIC ROCHESTER · 2020 · $146,459

## Abstract

Abstract
Liver cirrhosis is the leading cause of end-stage liver disease. A hallmark of cirrhosis is fibrogenesis: secretion
and deposition of excess extracellular matrix (ECM) proteins by hepatic stellate cells (HSCs). Prominent
among secreted ECM proteins is collagen I. Although the role of collagen I deposition in cirrhosis is well
known, therapies aimed at disrupting fibrogenesis are lacking. This is due in part to our poor understanding of
procollagen I trafficking through the secretory pathway. Fibrogenic signals such as TGFβ drive expression of
the collagen I precursor procollagen I, which is subsequently cotranslationed into the endoplasmic reticulum
(ER). Procollagen I fibrils oligomerize within the ER, forming a complex too large (~300nm) to package into
canonical ER export vesicles (60-90nm). Thus, additional, unknown cellular machinery is necessary for
procollagen I trafficking. If this machinery is disrupted, procollagen fibrils would be retained in the ER and lead
to ER stress, activation of the unfolded protein response (UPR), and possibly apoptosis. Recent elegant
studies performed in non-liver cells suggested that TANGO1 is critical for the transport of procollagens.
Whether TANGO1 facilitates ER export and secretion of collagen I from HSCs, a critical step in fibrogenesis, is
unknown. We hypothesize that TANGO1 drives procollagen I export from the ER, requires UPR
signaling to mediate this effect, and together TANGO1 and the UPR are critical for fibrogenesis in vivo.
This hypothesis is based on preliminary data showing (a) TANGO1 knockdown disrupts procollagen I ER
export, leading to UPR signaling and HSC apoptosis, (b) TANGO1 expression is mediated, at least in part, by
the UPR-activated transcription factor XBP1, and (c) TANGO1+/- mice are protected from cirrhosis
development. The novelty and relevance of studying the role of TANGO1 in procollagen I trafficking and its
regulation are two-fold: 1) we can identify new targets to disrupt collagen I secretion in fibrogenesis, and 2)
failure to resolve ER stress driven by procollagen I retention may lead to HSC apoptosis. The latter mechanism
is favorable for fibrosis resolution. Our long-term goal is to elucidate mechanisms of procollagen I trafficking
within HSCs and identify novel therapeutic targets to treat liver cirrhosis. The research proposed here will
utilize rigorous in vitro and in vivo approaches to unveil the mechanisms of TANGO1-mediated procollagen I
trafficking in HSCs, the regulatory relationship between TANGO1 and the UPR during HSC activation, and
finally the role of TANGO1 and the UPR in fibrogenesis and fibrosis regression.

## Key facts

- **NIH application ID:** 9841394
- **Project number:** 5K01DK112915-03
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Jessica L Maiers
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $146,459
- **Award type:** 5
- **Project period:** 2018-02-05 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9841394

## Citation

> US National Institutes of Health, RePORTER application 9841394, Regulation of Hepatic Fibrogeneiss by TANGO1 (5K01DK112915-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9841394. Licensed CC0.

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