Thursday, April 18, 2024
4/18/2024
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 TGFß 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.
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