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LAP1 interactome profiling provides new insights into LAP1’s physiological functions

ABSTRACT: The nuclear envelope (NE), a protective membrane bordering the nucleus, is composed of highly specialized proteins that are indispensable for normal cellular activity. Lamina-associated polypeptide 1 (LAP1) is a NE protein whose functions are just beginning to be unveiled. The fact that mutations causing LAP1 deficiency are extremely rare and pathogenic is indicative of its paramount importance to preserve human health, anticipating that LAP1 might have a multifaceted role in the cell. Mapping the LAP1 protein interactome is, thus, imperative to achieve an integrated view of its potential biological properties. To this end, we employed in silico- and mass spectrometry-based approaches to identify candidate LAP1-interacting proteins, whose functional attributes were subsequently characterized using bioinformatics tools. Our results suggest that LAP1 may participate in cellular processes as diverse as chromatin and cytoskeleton organization, DNA repair, RNA processing, translation as well as protein biogenesis and turnover. Novel interactions between LAP1 and DNA repair proteins were additionally validated, strengthening the previously proposed involvement of LAP1 in the maintenance of genomic stability. Overall, the data presented in this study reaffirm the biological relevance of LAP1 and the need to deepen our knowledge about this NE protein, providing new insights that will help guiding future research towards a mechanistic understanding of LAP1’s functioning.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: guadalupe espadas

LAB HEAD: Eduard Sabidó

PROVIDER: PXD056445 | Pride | 2025-01-13

REPOSITORIES: pride

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			Action	DRS
	2022LB025_CATI_001_01_10pto.msf	Msf
	2022LB025_CATI_001_01_10pto.raw	Raw
	2022LB025_CATI_002_01_10pto.msf	Msf
	2022LB025_CATI_002_01_10pto.raw	Raw
	2022LB025_CATI_003_01_10pto.msf	Msf

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Project description:DHX15 is an ATP-dependent RNA helicase involved in pre-mRNA splicing. We have recently reported that DHX15 is a downstream substrate for Akt1, which plays a significant role in vascular biology. Therefore, we aimed to explore the regulatory function of DHX15 over the vasculature, and the endothelial cell biology in different contexts: development, metabolism, ischemia and tumor growth. Methods: Deficient DHX15 mice and zebrafish were generated using transcription activator-like effector nuclease (TALEN) and Crispr/cas9 gene edition. Lymphatic functionality was evaluated by lymphangiography and magnetic resonance imaging. Mouse-induced tumor and metastasis model were generated by injection of syngeneic LLC1 tumor cells. DHX15 gene silencing in mouse liver endothelial cells (LEC) was performed by the lentiviral transduction of shRNA (Dharmacon). The changes in the transcriptome and the proteome resulting from the shRNA transduction were investigated by RNAseq and mass spectrometry, respectively. Results: Homozygous DHX15 gene deficiency was lethal in mouse and zebrafish embryos. DHX15-/- zebrafish also showed an undeveloped parachordal line, which leads to the formation of lymphatic structures in the trunk during the development. DHX15+/- mice and zebrafish were viable, although DHX15+/- gene deficiency triggered lower vascular network density and impaired lymphatic function postnatally in mice. Whole transcriptome and proteome analysis of DHX15 silenced LEC revealed differential expression of enzymes involved in the glycolysis and the gluconeogenesis pathways. The functional validation of these results demonstrated an uncoupling of the glycolysis with the oxidation of pyruvate into the mitochondria and lower activity of the Complex I in the mitochondrial membrane, resulting in lower cellular ATP production. Noteworthy, heterozygous DHX15 deficiency partially inhibited primary tumor growth and reduced lung metastasis after injection of syngeneic LLC1 tumor cells, compared to wild-type mice

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LAP1 interactome profiling provides new insights into LAP1’s physiological functions

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