Loss of Sun2 ablates nuclear mechanosensing-driven extracellular matrix production and mitigates lung fibrosis

Emma Carley, Sandra Sandria, Xueyan Peng, Kerri Davidson, Aya Nassereddine, Changwan Ryu, Rachel Rivera, John McGovern, Alexander Ghincea, C. Patrick Lusk, Erica L. Herzog, Valerie Horsley, Megan C. King

Posted on: 13 May 2026

Preprint posted on 20 March 2026

Sun2: the great separator of healthy tissue repair and pathological fibrosis?

Selected by Beth Chopak

Categories: biophysics, cell biology

Summary:

Sun2 emerges as a surprisingly specific driver of fibrosis; its loss leaves fibroblasts activated but unable to produce excessive ECM proteins or drive disease. This represents an uncoupling of fibroblast activation and ECM output, and an exciting potential therapeutic angle.

Figure 1: A graphical abstract. In the absence of Sun2, whilst TGFβ signalling, and fibroblast activation occurs normally, excessive ECM production is inhibited. Created in BioRender: https://BioRender.com/hbdv9ma

The Main Story:

Fibrosis is defined as a pathogenic increase in tissue stiffness which can arise when normal wound healing becomes excessive: fibroblasts, which are essential for tissue repair, deposit extracellular matrix (ECM) proteins to restore integrity after injury. However, when this response is not properly resolved, excessive ECM production leads to tissue stiffening, loss of function, and ultimately organ failure. Fibrosis involves the same cellular machinery as healthy repair, thereby presenting a challenging therapeutic target.

Mechanical cues are sensed by B1 integrin-based focal adhesions: these adhesions then facilitate the transmission of mechanical signals to the actomyosin cytoskeleton. These signals are then transmitted to the nucleus via the LINC (Linker of Nucleus and Cytoskeleton) complex: Sun2 is a key component of this LINC complex.

In this preprint, Carley and colleagues have demonstrated for the first time that the ablation of Sun2 blunts the production of pathogenic ECM proteins from fibroblasts, whilst, crucially, not influencing fibroblast activation or TGFβ biochemical signalling pathways. This implicates Sun2 as a critical regulator linking mechanical stimulation to fibrosis-causing ECM production: this reveals that fibroblast activation and ECM production can be uncoupled – and that targeting this separation may offer a route to treat fibrosis without blocking tissue repair.

Main Findings:

The LINC complex component SUN2 is upregulated in human lung fibrosis

Firstly, Carley and colleagues immunostained lung sections of healthy patients vs those with fibrotic lung disease. Activated fibroblasts expressed high levels of smooth muscle actin (a-SMA): in regions with high a-SMA, Sun2 was concurrently expressed at higher levels. Similar results were observed in injury-induced fibrosis in mice, and altogether, implicate elevated Sun2 as a hallmark of fibrosis.

Sun2 levels are regulated post-transcriptionally

Using hydrogels to mimic substrates of different stiffness, Sun2 levels were then measured in these different mechanical contexts. Whilst levels of Sun2 intensity in the nuclear envelope did increase with substrate stiffness, there was no difference in the Sun2 genetic transcripts. This therefore suggests that levels of Sun2 are regulated post transcriptionally.

Sun2 deficiency reduces effects of lung fibrosis

Sun2^-/-mice were then compared to wild-type mice in their response to injury-induced fibrosis; whilst there did not seem to be an immediate impact, at 14 days after the injury, Sun2^-/- mice had a significantly lower measured level of soluble collagen – a key ECM protein – in the relevant tissues. This directly suggests that the absence of Sun2 conveys protection against the pathogenic production of excessive ECM in fibrosis. Fascinatingly, there was a sex difference in collagen levels of Sun^-/- mice: with female mice more likely to clear the collagen entirely. There is no obvious explanation for this interesting discrepancy.

Figure 2: Less Sun2^-/- fibroblasts produce pro-collagen. Determined by two-tailed unpaired t test; ***p < 0.001. From Carley et al (2026), https://www.biorxiv.org/content/10.64898/2026.03.18.712778v1.full

Sun2 is dispensable for initial injury response, re-establishment of the alveolar barrier, canonical TGFβ signalling, and the fibroblast to myofibroblast transition

Now here’s where it gets really interesting. After showing that Sun2 is required for pathogenic ECM deposition, Carley and colleagues then demonstrated that Sun2 was not required for almost all other functions of fibroblasts. This included TGFβ signalling, which is the main signalling pathway in fibroblast activation. Smad proteins are the transcription factors responsible for fibroblast activation, and were shown to have no difference in nuclear localisation patterns even in the absence of Sun2, indicating that the TGFβ signalling pathway was intact in these cells. Additionally, a key part of wound healing is the conversion of fibroblasts to myofibroblasts, which then facilitate contractility: this transition of cellular types was unaffected in Sun2^-/- cells.

Figure 3: There is no significant difference between the size of the gel contracted by wildtype lung fibroblasts and Sun2^-/- fibroblasts after 24 hours as determined by two-tailed unpaired t-test. N=6. From Carley et al (2026), https://www.biorxiv.org/content/10.64898/2026.03.18.712778v1.full

What this all means:

Taken altogether, these experiments indicate that Sun2 is a key modulator of the fibroblast response. While TGFβ signalling remains intact in the absence of Sun2, mechanically induced transcription is lost; positioning Sun2 as a specific requirement for mechanically driven ECM gene expression.

Why this matters:

There is currently no treatment for pathogenic fibrosis, as fibroblasts are required for wound healing in healthy tissue, and decoupling pathogenic ECM deposition from healthy wound healing has proved challenging. This preprint, for the first time, presents a potential mechanism of decoupling these processes: ultimately offering an opportunity for potential anti-fibrosis treatment.

Tags: fibrosis, linc complex, mechanobiology, mechanotransduction

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A chat with the authors

Sandra Sandria shared

I had the pleasure of chatting with Sandra Sandria, a joint first author of this paper, and asking some of the more outstanding questions raised:

Is it just Sun2 that has this remarkable effect? What about Sun1, which has also been shown to be a part of the LINC complex?

There is absolutely a chance that Sun1 influences the described system, and this will likely be addressed in follow-up experiments. Currently however, there are some barriers to experimentation: a double Sun1/Sun2 KO in mice is lethal, and Sun1 antibodies limited in efficacy.

Is it likely that these observations are the result of Sun2 itself, or more a result of impaired LINC complex function? If so, could experiments involving other components of the LINC complex bear similar results?

The current model is one of chromatin remodelling as a result of Sun2 mediated mechanotransduction: follow-up experiments will also include investigations into other components of the LINC complex. One potential investigative route is the use of a double-negative KASH domain: essentially nesprin, but without the KASH domain which binds Sun2. This will give further detail into the mechanism by which the LINC complex influences ECM production.

Are there potential side-effects of a reduction in ECM production that might prove pathological?

Experiments conducted thus far suggest not: that is the more remarkable feature of the Sun2^-/-phenotype, in that epithelial repair remains intact, suggesting that there is a strikingly clear delineation between tissue repair and pathogenic ECM production.

The sex difference in collagen outcomes is intriguing – do you think this is more likely a result of genetic or hormonal differences?

Again, definitely something to be looked into, but the main theory is that this is likely the result of a hormonal difference, and research is being done into potential sex-based differences in collagen production.

Was there a particular experiment that made you realise this research was heading somewhere particularly promising?

The first immunostaining which demonstrated that regions of high A-SMA had a significant correlation with elevated Sun2. This striking correlation was the first indicator of something really exciting.

What next?

The paper has been submitted for peer-review. The first priority will therefore be to address any reviewers comments, and likely look at different components of the LINC complex. Ultimately however, mechanistic detail is the goal. This paper has demonstrated that Sun2 influences pathogenic ECM production, but details of the mechanism which drives this are yet to be elucidated.

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