Zhu, Ming et al. (2020) MicroPubl Biol

Jin, Yishi, Chisholm, Andrew D, Zhu, Ming

[MicroPubl Biol, 2020]

VWA8 proteins, named for von Willebrand factor A (VWA) domain containing 8, are conserved from worm to mammals (Whittaker & Hynes, 2002). In mouse, vwa8 gene produces long and short protein isoforms (VWA8a and VWA8b), and in rat livers VWA8a has been shown to localize to the matrix side of inner mitochondrial membrane (Luo et al., 2020). C. elegans vwa-8 is also predicted to produce two major protein isoforms. The short isoform (974 AA) shares identical AA sequences as the long isoform (1804 AA). The two isoforms contain an MTS (mitochondrial targeting sequence) at the N terminus, followed by three AAA ATPase domains, which are associated with diverse cellular activities; and the long isoform contains a VWA domain at the C terminus. To determine the endogenous expression pattern of C. elegans VWA-8, we generated a GFP knock-in allele, ju1799, in which GFP was in-frame fused at the C terminus to label the full-length protein specifically. The endogenous VWA-8::GFP was expressed in mitochondria of hypodermis, intestine and muscle, but was not detectable in neurons (Fig 1A). In hypodermis, VWA-8::GFP was colocalized with MitoTracker Red, a mitochondria marker (Fig 1B).

Zhu, Ming et al. (2020) MicroPubl Biol

Zhu, Ming, Chisholm, Andrew D, Jin, Yishi

[MicroPubl Biol, 2020]

VWA8 proteins, named for von Willebrand factor A (VWA) domain containing 8, are conserved from worm to mammals (Whittaker & Hynes, 2002). In human, two SNPs (rs9566845 and rs9566867) in vwa8 are found to be associated with bipolar disorder with comorbid migraine (Oedegaard et al., 2010). Another SNP (rs9532931) is tentatively associated with a specific sub-group of autism patients (Anney et al., 2010). The C. elegans VWA-8 long isoform shares 38% and 55% amino acid sequence identity and similarity, respectively, with human VWA8 long isoform. We showed that endogenous VWA-8 is expressed in mitochondria of somatic tissues, except neurons (Zhu, Chisholm & Jin, 2020). To determine the function of C. elegans vwa-8, we generated a null allele vwa-8(ju1659) by CRISPR-Cas9. vwa-8(ju1659) mutants are homozygous viable, and indistinguishable from wild type in gross phenotypes such as body size, brood size, growth rate and movement.

Yeh CY et al. (2021) Dev Cell "A leucine-derived fatty acid unlocks the mTOR to development."

Yeh CY, Lamming DW

[Dev Cell, 2021]

Understanding how nutrient-sensitive signaling pathways regulate development and aging is an active area of research. In this issue of Developmental Cell,Zhu and colleagues (2021) identify a specific monomethylated branched-chain fatty acid that overrides nutrient deprivation signaling and activates mTORC1 in C.elegans and mammalian cells.

Molinie N et al. (2016) Dev Cell "WASP and WAVE Team Up at the Leading Edge."

Molinie N, Gautreau A

[Dev Cell, 2016]

Arp2/3-dependent branched actin networks drive membrane protrusions, with WAVE being recognized as the critical Arp2/3 activator in this process. In this issue of Developmental Cell, Zhu etal. (2016) demonstrate that WASP, an Arp2/3 activator mostly involved in endocytosis, collaborates with WAVE to promote migration of neuroblasts in Caenorhabditis elegans.

He XY et al. (1998) J Biol Chem "A human brain L-3-hydroxyacyl-coenzyme A dehydrogenase is identical to an amyloid beta-peptide-binding protein involved in Alzheimer's disease."

He XY, Schulz H, Yang SY

[J Biol Chem, 1998]

A novel L-3-hydroxyacyl-CoA dehydrogenase from human brain has been cloned, expressed, purified, and characterized. This enzyme is a homotetramer with a molecular mass of 108 kDa. Its subunit consists of 261 amino acid residues and has structural features characteristic of short chain dehydrogenases. It was found that the amino acid sequence of this human brain enzyme is identical to that of an endoplasmic reticulum amyloid beta-peptide-binding protein (ERAB), which mediates neurotoxicity in Alzheimer's disease (Yan, S. D., Fu, J., Soto, C., Chen, X., Zhu, H., Al-Mohanna, F., Collison, K., Zhu, A., Stern, E., Saido, T., Tohyama, M., Ogawa, S., Roher, A., and Stern, D. (1997) Nature 389, 689-695). The purification of human brain short chain L-3-hydroxyacyl-CoA dehydrogenase made it possible to characterize the structural and catalytic properties of ERAB. This NAD+-dependent dehydrogenase catalyzes the reversible oxidation of L-3-hydroxyacyl-CoAs to form 3-ketoacyl-CoAs, but it does not act on the D-isomers. The catalytic rate constant of the purified enzyme was estimated to be 37 s-1 with apparent Km values of 89 and 20 microM for acetoacetyl-CoA and NADH, respectively. The activity ratio of this enzyme for substrates with chain lengths of C4, C8, and C16 was approximately 1:2:2. The human short chain L-3-hydroxyacyl-CoA dehydrogenase gene is organized into six exons and five introns and maps to chromosome Xp11.2. The amino-terminal NAD-binding region of the dehydrogenase is encoded by the first three exons, whereas the other exons code for the carboxyl-terminal substrate-binding region harboring putative catalytic residues. The results of this study lead to the conclusion that ERAB involved in neuronal dysfunction is encoded by the human short chain L-3-hydroxyacyl-CoA dehydrogenase gene.