A NEAT Discovery Hints at Altered Golgi Signaling in Lung Fibrosis

Within a eukaryotic cell, compartmentalization into organelles generates multiple specialized microenvironments that allows highly efficient activities within confined boundaries. Organelle homeostasis is crucial for cell survival and function, and organelle dysfunction or impaired organelle crosstalk frequently contributes to the onset or progression of disease. Over the past two decades, downstream signaling cascades associated with organelle dysfunction have emerged as key elements in fibrogenesis: Endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) in type II alveolar epithelial (AT2) cells increase susceptibility to lung injury and promote fibrotic remodeling (1–4). Similarly, mitochondrial dysfunction—in particular, in AT2 cells of the aging lung—contributes to fibrogenesis (5, 6). A disease- and/or aging-associated impairment of proteostasis mechanisms (e.g., compromised autophagy and altered proteasome activity) generates an additional profibrotic loop in this context, because damaged organelles and proteins are not cleared efficiently (7–10).

In addition to well-established organelle dysfunction pathways in lung fibrosis, Golgi signaling and Golgi stress have received surprisingly little attention. This is despite Golgi function being linked to both ER and mitochondria, with the Golgi network serving as the trafficking route for lysosomal, extracellular, and membrane proteins, and through a direct linked to the rough ER, where these proteins are synthesized. One of the key UPR signaling pathways, the ATF6 pathway, is dependent on cell membrane–to-Golgi translocation and ATF6 processing in the Golgi, generating a transcription factor that shuttles to the nucleus and activates UPR target genes (11, 12). More recent work has also identified direct contacts between Golgi and mitochondria that are thought to facilitate lipid import from the Golgi during mitochondrial respiration (13). However, research exploring the impact of Golgi dysfunction on fibrogenesis is limited. A few studies suggest a dual nature for Golgi disruption, with detrimental impacts that are due to the induction of autophagy in epithelial cells, and potentially beneficial effects by inhibiting excessive extracellular matrix (ECM) secretion. For instance, loss of Golgin subfamily A member 2 (GOLGA2), an important structural cis-Golgi matrix component, promotes fibrogenesis in liver and lung through the induction of autophagy and Golgi disruption (14). In contrast, Golgi-targeted nanomicelles, designed to destroy Golgi structure in hepatic stellate cells, have proven beneficial in in vitro and in vivo models of liver fibrogenesis through the inhibition of procollagen secretion (15). Finally, the COPA syndrome, an autoimmune disease frequently resulting in interstitial lung disease and caused by deleterious variants of COPA, provides genetic evidence that supports a link between Golgi dysfunction and lung fibrosis. The COPA gene encodes coatomer subunit α, a constituent of COPI vesicles essential for retrograde protein transport from the Golgi to the ER (16).

In this issue of the Journal, Wang and colleagues (pp. 178–192) report Golgi membrane protein 1 (GOLM1; also termed GOLPH2 or GP73) as an important regulator of lung fibrogenesis (17). Using publicly available single-cell and bulk RNA-sequencing data sets and patient samples, the authors show overexpression of GOLM1 in idiopathic pulmonary fibrosis. Using an elegant series of loss- and gain-of-function experiments in vitro and in vivo, the authors effectively demonstrate that GOLM1 promotes fibroblast proliferation, migration, and ECM production. Their research then delves deep into elucidating downstream mechanisms of GOLM1, and, using overexpression and silencing of GOLM1 in human pulmonary fibroblasts, they identify a long noncoding RNA, NEAT1, the expression of which strongly and positively correlates with GOLM1 expression. Moreover, overexpressing or silencing NEAT1 in human pulmonary fibroblasts partially counteracted the effect of silencing or overexpressing GOLM1, respectively, both in terms of profibrotic gene expression and proliferation. As this strongly suggests that the profibrotic function of GOLM1 is mediated by NEAT1, the authors went on to explore potential transcription factors that may regulate NEAT1 expression. Using mutational promoter analysis in combination with a luciferase gene expression reporter system, as well as chromatin immunoprecipitation, the authors convincingly identify Krüppel-like factor 4, or KLF4, as a negative regulator of NEAT1. Hence, the study puts forward the GOLM1-KLF4-NEAT1 signaling axis as a completely novel potential therapeutic strategy in lung fibrosis. In addition, their findings indicate that serum levels of soluble GOLM1 (sGOLM1) may be suitable as a prospective peripheral marker for monitoring therapeutic responses in this context, further strengthening the potential clinical application of the findings.

Although the authors deserve praise for their meticulous and comprehensive approach, a closer examination of the study unveils areas that call for further exploration. An emphasis on fibroblasts in vitro is justified because of their central role as effector cells in lung fibrosis, but it is interesting to note that GOLM1 expression in epithelial cells—specifically in ionocytes and in secretory and basaloid cells—appears more pronounced than in fibroblasts. This suggests that they could hold even more relevance in understanding the role of GOLM1 in disease pathogenesis. Given the growing interest in airway epithelial cells as potential sites initiating or driving fibrogenesis (18), exploring this area may be particularly intriguing. Moreover, the precise mechanisms, including the potential impact of GOLM1 overexpression on Golgi morphology, Golgi function, and interorganelle communication, remain incompletely clarified. This would be interesting to explore, as the Golgi plays a pivotal role in the trafficking, processing, and secretion of a plethora of extracellular proteins with central functions in fibrosis, including collagen and other ECM proteins (19); profibrotic cytokines; surfactant proteins; and, last but not least, mucin 5B (MUC5B) (20).

Despite a more routine focus on ER stress and the UPR, Golgi stress is increasingly becoming recognized as a mechanism triggering distinct downstream signaling cascades in response to various stressors (21). For instance, the Golgi membrane protein Golgi phosphoprotein 3 (GOLPH3) has been identified as an important player in mediating morphological changes of the Golgi and downstream signaling pathways after cellular stress and injury (22, 23). Undoubtedly, unveiling mechanisms that trigger the overexpression of GOLM1, as well as investigating the association between GOLM1, Golgi morphology, and Golgi signaling in depth, may lead to additional important insights. In conclusion, in the context of these emerging concepts, the study by Wang and colleagues (17) raises compelling questions that clearly warrant further studies into the role of Golgi stress, dysfunction, and signaling, as well as the associated interorganelle crosstalk in lung fibrosis.