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SMALL REGULATORY POLYPEPTIDE OF AMINO ACID RESPONSE; SPAAR

SMALL REGULATORY POLYPEPTIDE OF AMINO ACID RESPONSE; SPAAR

Alternative titles; symbolsSPARLONG INTERGENIC NONCODING RNA 961; LINC00961lincRNA 961HGNC Approved Gene Symbol: SPAARCytogenetic location: 9p13.3 Genomic co...

Alternative titles; symbols

  • SPAR
  • LONG INTERGENIC NONCODING RNA 961; LINC00961
  • lincRNA 961

HGNC Approved Gene Symbol: SPAAR

Cytogenetic location: 9p13.3 Genomic coordinates (GRCh38): 9:35,909,489-35,911,685 (from NCBI)

▼ Description
Long noncoding RNAs (lncRNAs) are transcribed by RNA polymerase II and are splice, capped, and polyadenylated. A subset of transcripts classified as lncRNAs, including SPAAR, encode polypeptides with fewer than 100 amino acids. The SPAAR polypeptide has a role in nutrient sensing and negatively regulates activation of mTOR complex-1 (mTORC1; see 601231) by amino acids (Matsumoto et al., 2017).

▼ Cloning and Expression
Matsumoto et al. (2017) identified an ORF within SPAAR, which they called SPAR, predicted to encode a 90- or 75-amino acid polypeptide depending on the initiation codon used. Both polypeptides have a conserved N-terminal transmembrane domain and a cytosolic C terminus. Mouse Spar contains only 1 initiating methionine and encodes a 75-amino acid polypeptide that shares 65% identity with the shorter human polypeptide. Quantitative PCR of 20 human tissues detected highest SPAR expression in placenta, with lower expression in lung, skeletal muscle, and heart, and little to no expression in other tissues examined. Of 12 mouse tissues, highest Spar expression was detected in heart, followed by skeletal muscle, testis, lung, and kidney. Epitope-tagged human SPAR colocalized with a marker of lysosomes and late endosomes in transfected HeLa and PC3 cells. Western blot analysis of mouse skeletal muscle revealed an apparent 10-kD protein in the pelleted membrane fraction.

▼ Mapping
Hartz (2017) mapped the SPAAR gene to chromosome 9p13.3 based on an alignment of the SPAAR sequence (GenBank AK056723) with the genomic sequence (GRCh38).

▼ Gene Function
Using immunoprecipitation analysis, Matsumoto et al. (2017) found that epitope-tagged SPAR interacted with the V0A1 (ATP6V0A1; 192130) and V0A2 (ATP6V0A2; 611716) subunits of the lysosomal V-ATPase, which negatively regulates mTORC1 activation. A SPAR transcript containing the SPAR coding region, but not one lacking initiating methionines, inhibited amino acid stimulation of mTORC1 in HeLa and PC3 cells. SPAR did not influence mTORC1 activation by growth factors or stimuli other than amino acids. Overexpression of SPAR caused failure of mTORC1 to relocalize to lysosomes in response to amino acid stimulation. Conversely, knockdown of SPAR in HeLa cells increased activation of mTORC1 upon amino acid stimulation. Inhibitor studies suggested that SPAR functions at the level of the V-ATPase.

▼ Animal Model
Using CRISPR/Cas9 engineering, Matsumoto et al. (2017) developed mice with an ATG mutation that ablated Spar polypeptide expression without loss of the host RNA. Spar -/- mice were born at the expected mendelian ratio and were indistinguishable from wildtype littermates. Spar -/- skeletal muscle expressed the host RNA, but not the Spar polypeptide. Spar -/- muscle showed hyperactivation of mTORC1 following cardiotoxin-mediated injury, with increased rate of repair, muscle size, and stem cell proliferation capacity. Matsumoto et al. (2017) concluded that Spar inactivation promotes muscle regeneration through increased mTORC1 activation, which in turn promotes stem cell proliferation, differentiation, and myofiber maturation.

Tags: 9p13.3