Dataset Information

Loss of POGLUT2 and 3 eliminates O-glucose at predicted sites but does not alter other modifications on EGFs

ABSTRACT: Fibrillins play a critical role in tissue/organ development and cardiopulmonary function. Here we showed that O-glucosylation of the fibrillins’ epidermal growth factor-like repeats by protein O-glucosyltransferase 2 (POGLUT2) and POGLUT3 was indispensable for in vivo function of mouse fibrillins. Loss of O-glucosylation of fibrillins caused neonatal death with cardiopulmonary, skeletal, and eye defects reminiscent of fibrillin/elastin mutations. Analyses of FBNs in Poglut2/3 double knockout (DKO) lung, and from DKO dermal fibroblast medium and matrix, provided overwhelming evidence that fibrillins were more susceptible than other POGLUT2/3 substrates to loss of O-glucose. In the DKO, defects in microfibril structure impaired elastic fiber formation, reduced TGF-β/pERK signaling, caused structural defects in late gestation lung blood vessels and terminal bronchioles, and impaired cell differentiation and primary septation in the saccules/alveoli. Collectively, these data support an essential role for POGLUT2/3-mediated O-glucosylation in fibrillin trafficking, microfibril assembly/stability, and function in the ECM environment during lung development.

ORGANISM(S): Mus Musculus

SUBMITTER: Daniel Williamson

PROVIDER: PXD043827 | panorama | Mon Jun 10 00:00:00 BST 2024

REPOSITORIES: PanoramaPublic

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Poglut2/3 double knockout in mice results in neonatal lethality with reduced levels of fibrillin in lung tissues.

Neupane Sanjiv S Williamson Daniel B DB Roth Robyn A RA Halabi Carmen M CM Haltiwanger Robert S RS Holdener Bernadette C BC

The Journal of biological chemistry 20240604 7

Fibrillin microfibrils play a critical role in the formation of elastic fibers, tissue/organ development, and cardiopulmonary function. These microfibrils not only provide structural support and flexibility to tissues, but they also regulate growth factor signaling through a plethora of microfibril-binding proteins in the extracellular space. Mutations in fibrillins are associated with human diseases affecting cardiovascular, pulmonary, skeletal, and ocular systems. Fibrillins consist of up to 4 ...[more]

PMID: 38844137

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Project description:This experiment was conducted to identify the mitochondrial protein changes in the presence and absence of LONP1 in skeletal muscle. The following abstract from the submitted manuscript describes the major findings of this work.Disuse-associated loss of muscle LONP1 impairs mitochondrial quality and causes reduced skeletal muscle mass and strength. Zhisheng Xu, Tingting Fu, Qiqi Guo, Danxia Zhou, Wanping Sun, Zheng Zhou, Lin Liu, Liwei Xiao, Yujing Yin, Yuhuan Jia, Xin Pan, Lei Fang, Min-sheng Zhu, Wenyong Fei, Bin Lu and Zhenji Gan. Mitochondrial proteolysis is an evolutionarily conserved quality control mechanism to maintain proper mitochondrial integrity and function. However, the physiological relevance of stress-induced impaired mitochondrial protein quality remains unclear. Here, we demonstrate that LONP1, a major mitochondrial protease resides in the matrix, plays a critical role in controlling mitochondrial quality as well as skeletal muscle mass and strength in response to muscle disuse. In humans and mice, disuse-related muscle loss is associated with decreased mitochondrial LONP1 protein. Skeletal muscle-specific ablation of LONP1 in mice resulted in impaired mitochondrial protein turnover, leading to mitochondrial dysfunction. This caused reduced muscle fiber size and strength. Mechanistically, aberrant accumulation of mitochondrial-retained protein in muscle upon loss of LONP1 induces the activation of autophagy-lysosome degradation program of muscle loss. Overexpressing a mitochondrial-retained mutant ornithine transcarbamylase (ΔOTC), a known protein degraded by LONP1, in skeletal muscle induces mitochondrial dysfunction, autophagy activation, and cause muscle loss and weakness. Thus, these findings reveal a pivotal role of LONP1-dependent mitochondrial protein quality-control in safeguarding mitochondrial function and preserving skeletal muscle mass and strength, and unravel an intriguing link between mitochondrial protein quality and muscle mass maintenance during muscle disuse.

Dataset Information

Loss of POGLUT2 and 3 eliminates O-glucose at predicted sites but does not alter other modifications on EGFs

Publications

Poglut2/3 double knockout in mice results in neonatal lethality with reduced levels of fibrillin in lung tissues.

Similar Datasets

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