LAPTM4B Alleviates Pulmonary Fibrosis by Enhancing NEDD4L-Mediated TGF-β Signaling Suppression
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eLife Assessment
In this valuable manuscript, the authors propose that the lysosomal protein LAPTM4B plays a role in suppressing the TGF-β/SMAD signaling pathway and suggest that enhancing LAPTM4B function could be a potential therapeutic strategy for alleviating bleomycin-induced lung fibrosis. The findings will be of interest to the lung disease field, and the data presented to support the authors' conclusions is solid. However, it remains unclear whether the suppressive effect of LAPTM4b on idiopathic pulmonary fibrosis is mediated by Nedd4l.
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Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease with fatal outcome and a poorly understood pathogenesis. The lysosomal protein transmembrane 4 beta (LAPTM4B), a multi-transmembrane endo-lysosomal membrane protein, has been implicated in the pathogenesis of several diseases. However, its involvement in IPF remains unexplored. This study aimed to investigate the role of LAPTM4B in lung fibrosis and elucidate its underlying mechanisms. The results showed that LAPTM4B was significantly reduced in IPF and mouse fibrotic lungs. In vivo studies showed that the deficiency of LAPTM4B exacerbated bleomycin-induced lung fibrosis, while the restoration of LAPTM4B alleviated fibrosis. Mechanistically, LAPTM4B recruits the NEDD4 like E3 ubiquitin protein ligase (NEDD4L) to endosomes, leading to increased ubiquitin-mediated proteasomal degradation of TGFRB2 and active SMAD2/3, thereby blocking the TGF-β/SMAD signaling pathway. Overall, our data provided a novel insight for a deeper understanding of the pathogenesis of IPF, supporting the therapeutic potential of restoration of LAPTM4B as a promising therapeutic approach for the treatment of pulmonary fibrosis.
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eLife Assessment
In this valuable manuscript, the authors propose that the lysosomal protein LAPTM4B plays a role in suppressing the TGF-β/SMAD signaling pathway and suggest that enhancing LAPTM4B function could be a potential therapeutic strategy for alleviating bleomycin-induced lung fibrosis. The findings will be of interest to the lung disease field, and the data presented to support the authors' conclusions is solid. However, it remains unclear whether the suppressive effect of LAPTM4b on idiopathic pulmonary fibrosis is mediated by Nedd4l.
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Reviewer #1 (Public review):
Summary:
In this manuscript, the authors propose that LAPTM4B plays a role in suppressing the TGF-β/SMAD signaling pathway and suggest that enhancing LAPTM4B function could be a potential therapeutic strategy for alleviating BLM-induced lung fibrosis. Their data show that LAPTM4B knockdown exacerbates fibrosis phenotypes, both in vivo and in vitro, while LAPTM4B overexpression mitigates these effects by recruiting NEDD4L to destabilize SMAD proteins.
Strengths:
The findings are significant for the lung disease field, and the data presented support the authors' conclusions. This work would be of even higher interest after sufficiently addressing the weaknesses listed below.
Weaknesses:
Several issues need to be addressed. First, it is unclear why the authors chose to focus on LAPTM4B specifically, rather than …
Reviewer #1 (Public review):
Summary:
In this manuscript, the authors propose that LAPTM4B plays a role in suppressing the TGF-β/SMAD signaling pathway and suggest that enhancing LAPTM4B function could be a potential therapeutic strategy for alleviating BLM-induced lung fibrosis. Their data show that LAPTM4B knockdown exacerbates fibrosis phenotypes, both in vivo and in vitro, while LAPTM4B overexpression mitigates these effects by recruiting NEDD4L to destabilize SMAD proteins.
Strengths:
The findings are significant for the lung disease field, and the data presented support the authors' conclusions. This work would be of even higher interest after sufficiently addressing the weaknesses listed below.
Weaknesses:
Several issues need to be addressed. First, it is unclear why the authors chose to focus on LAPTM4B specifically, rather than other members of the LAPTM family, such as LAPTM4A or LAPTM5. Additionally, the manuscript does not address whether lysosomes are involved in the degradation of ubiquitinated LAPTM4B.
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Reviewer #2 (Public review):
Summary:
It was previously documented that lysosomal localization of the Lysosomal transmembrane proteins LAPTM4 or 5 (including LAPTM4b) is regulated by Nedd4 family ubiquitin ligases, and independently, that Nedd4l regulates IPF (Idiopathic Pulmonary Fibrosis) in mouse lungs via regulation of the TGFb pathway (ie, Nedd4l lung-specific KO mice develop IPF due to reduced ability to suppress the TGFb pathway -PMID: 32332792 ). Here, Xu et al investigated the role of LAPTM4b in IPF and suggested that the suppression of IPF by LAPTM4b, which they discovered here, is mediated via its interaction with Nedd4L, which normally suppresses TGFb signaling.
Strengths:
Overall, this is an interesting paper that identified for the first time a suppressive role of LAPTM4b in IPF, using both in vivo mouse models and cell …
Reviewer #2 (Public review):
Summary:
It was previously documented that lysosomal localization of the Lysosomal transmembrane proteins LAPTM4 or 5 (including LAPTM4b) is regulated by Nedd4 family ubiquitin ligases, and independently, that Nedd4l regulates IPF (Idiopathic Pulmonary Fibrosis) in mouse lungs via regulation of the TGFb pathway (ie, Nedd4l lung-specific KO mice develop IPF due to reduced ability to suppress the TGFb pathway -PMID: 32332792 ). Here, Xu et al investigated the role of LAPTM4b in IPF and suggested that the suppression of IPF by LAPTM4b, which they discovered here, is mediated via its interaction with Nedd4L, which normally suppresses TGFb signaling.
Strengths:
Overall, this is an interesting paper that identified for the first time a suppressive role of LAPTM4b in IPF, using both in vivo mouse models and cell culture studies.
Weaknesses:
(1) The most obvious shortcoming of this study is the lack of experimental evidence that the suppressive effect of LAPTM4b on IPF is mediated by Nedd4l.
(2) Along the same lines, despite the authors' claim, overexpression of Nedd4L in cells does not increase SMAD3 ubiquitination (Fig 6D), which is a marker of TGFbR activation. Likewise, in Fig 5E, SMAD2 seems to be ubiquitinated similarly in the presence or absence of LAPTM4b (despite claims that LAPTM4b promotes ubiquitination of SMAD2). Same for K48 ubiquitination of TGFbR (Figure 5H).
(3) How does LAPTM4b interact with SMAD2 or 3, or TGFbR?
(4) All immunofluorescence (IF) studies depict 1 or 2 cells, with no quantification or statistics.
(5) Some of the Western blots (WB) are also not quantified, so any claims of an effect cannot be evaluated without such quantification and statistics.
(6) In the IF studies showing lung tissue (eg Figure 1B), why is LAPTM4b (wildtype) localized to the plasma membrane instead of lysosomes/endosomes?
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