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Defect in cytosolic Neu2 sialidase abrogates lipid metabolism and impairs muscle function in vivo.

ABSTRACT: Sialic acid (SA) is present in glycoconjugates and important in cell-cell recognition, cell adhesion, and cell growth and as a receptor. Among the four mammalian sialidases, cytosolic NEU2 has a pivotal role in muscle and neuronal differentiation in vitro. However, its biological functions in vivo remain unclear due to its very low expression in humans. However, the presence of cytoplasmic glycoproteins, gangliosides, and lectins involved in cellular metabolism and glycan recognition has suggested the functional importance of cytosolic Neu2 sialidases. We generated a Neu2 knockout mouse model via CRISPR/Cas9-mediated genome engineering and analyzed the offspring littermates at different ages to investigate the in vivo function of cytosolic Neu2 sialidase. Surprisingly, knocking out the Neu2 gene in vivo abrogated overall lipid metabolism, impairing motor function and leading to diabetes. Consistent with these results, Neu2 knockout led to alterations in sialylated glycoproteins involved in lipid metabolism and muscle function, as shown by glycoproteomics analysis.

SUBMITTER: Oh M

PROVIDER: S-EPMC8881595 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Defect in cytosolic Neu2 sialidase abrogates lipid metabolism and impairs muscle function in vivo.

Oh Mijung M Ha Dae-In DI Son Chaeyeon C Kang Jeong Gu JG Hwang Heeyoun H Moon Su Bin SB Kim Minjeong M Nam Jihae J Kim Jung Soo JS Song Sang Yong SY Kim Yong-Sam YS Park Sangwoo S Yoo Jong Shin JS Ko Jeong-Heon JH Park Kyoungsook K

Scientific reports 20220225 1

Sialic acid (SA) is present in glycoconjugates and important in cell-cell recognition, cell adhesion, and cell growth and as a receptor. Among the four mammalian sialidases, cytosolic NEU2 has a pivotal role in muscle and neuronal differentiation in vitro. However, its biological functions in vivo remain unclear due to its very low expression in humans. However, the presence of cytoplasmic glycoproteins, gangliosides, and lectins involved in cellular metabolism and glycan recognition has suggest ...[more]

PMID: 35217678

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Project description:Increased sialylation is one of the hallmarks of ovarian cancer (OC) but its relation with programmed cell death is not known. Here we explored the molecular interplay between autophagy, apoptosis/anoikis, and aberrant-expression of the PI3K-Akt/mTOR pathway in the context of sialidase. OC is accompanied by low expression of cytosolic sialidase (Neu2) and ~10-fold more α2,6- than α2,3-linked sialic acids found through qPCR, western blot, and flow cytometry. Interestingly, Neu2 overexpression cleaved α2,6- and α2,3-linked sialic acids and reduced cell viability. Several autophagy-related molecules like LC3B/Atg3/Atg5/Atg7/Atg12/Atg16L1/Beclin1 were upregulated upon Neu2 overexpression. Atg5, a crucial protein for autophagosome formation, was desialylated by overexpressed Neu2. Desialylated Atg5 now showed enhanced association both with Atg12 and Atg16L1 leading to more autophagosome formation. Neu2-overexpressing cells exhibited extrinsic pathway-mediated apoptosis as reflected the in activation of Fas/FasL/FADD/Bid/caspase 8/caspase 6/caspase 3/PARP cleavage. There was also increased Bax, reduced Bcl2, and several cell-cycle molecules (CDK2/CDK4/CDK6/cyclin-B1/cyclin-E). Inhibition of autophagy using bafilomycin A1 or Beclin1 siRNA leads to reversal of Neu2-induced apoptosis suggesting their possible relationship. Additionally, overexpressed Neu2 inhibited growth factor-mediated signaling molecules involved in the PI3K/Akt-mTOR pathway probably through their desialylation. Furthermore, overexpressed Neu2 inhibited epithelial (ZO-1/Claudin1), mesenchymal (snail/slug), and cell-adhesion (integrin-β3/focal-adhesion kinase) molecules suggesting anchorage-dependent cell death (anoikis). Such changes were absent in the presence of bafilomycin A1 indicating the involvement of autophagy in Neu2-induced anoikis. The physiological relevance of our in vitro observations was further confirmed in the OC xenograft model. Taken together, it is the first report demonstrating that Atg5 is a sialoglycoprotein having α2,6- and α2,3-linked sialic acids and its desialylation by overexpressed Neu2 leads to its activation for autophagosome formation, which induced apoptosis/anoikis in OC.

Dataset Information

Defect in cytosolic Neu2 sialidase abrogates lipid metabolism and impairs muscle function in vivo.

Publications

Defect in cytosolic Neu2 sialidase abrogates lipid metabolism and impairs muscle function in vivo.

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