C5orf22

Chromosome 5 open reading frame 22 (c5orf22) is a protein-coding gene of poorly characterized function in Homo sapiens.^[5] The primary alias is unknown protein family 0489 (UPF0489).^[5]

C5orf22 is located on the positive strand of Chromosome 5 at 5P13.3, spanning 22,779 nucleotides, from base pair 31532275 to 31555053.^[6] C5orf22 encodes 9 total exons and contains 7 isoforms.^[5] Isoform variants differ in their exon configuration and untranslated region. Transcript variant 1 is the canonical isoform, encoding 442 amino acids across 9 exons.^[7]

C5orf22 displays ubiquitous RNA expression across tissue types from all 3 germ layers and from all phases of development in humans, mice, chickens, and zebrafish.^[5] There are statistically significant differences in RNA expression between select tissues, with skeletal muscle containing the greatest abundance (7.8 RPKM)^[5][9]

C5orf22 contains 1 predicted promoter directly upstream of the gene (GXP_55076).^[8] This promoter is 1,081 base pairs and partially overlaps with the 5’ untranslated region.^[8] GXP_55076 is assigned to all transcript variants.^[8] Transcription factor binding elements consist of TATA box binding elements, SMAD transcription factors, MAF/AP1 binding factors, and several others.^[8]

C5orf22 closest neighboring element is Drosha, a ribonuclease which is encoded by the minus strand proximal to C5orf22.^[5][10] Drosha is a double stranded endoribonuclease that assists with the first step of microRNA biogenesis.^[11]

C5orf22 contains 2 globular domains and 3 small disordered regions.^[12] The molecular-weight is approximately 50 kDa.^[13] The isoelectric point is 4.7.^[13] C5orf22 contains relatively average amino acid proportions compared to most proteins.^[14] There were no significant outliers in abundance of individual amino acids. C5orf22 contains several predicted post-translational modifications including phosphorylation sites, ubiquitination sites, glycosylation sites, SH2 domain, and a myristylation site.^[12]

C5orf22 is most likely to exist as a soluble protein located within the cytoplasm and nucleus.^[15] Amino acid sequence predictions and immunohistochemical staining support the localization of C5orf22 to cytoplasm and nucleus.^[9][16] Furthermore, amino acid sequence analysis indicated a predicted partial nuclear localization signal (NLS) from AA 175-185.^[17]

The precise function of C5orf22 is still unknown however it is hypothesized to be a component of a DNA splicing complex.^[18] Proteomic research implicated the protein product as a novel component of the WBP11/PQBP1 splicing complex which regulates expression of genes involved in a spectrum of processes ranging from DNA repair to immunomodulation.^[18] C5orf22 knockdown was associated with downregulation of alternative splicing events that led to aberrant gene expression of select genes and ultimately cell cycle dysfunction.^[18] Cell localization evidence and the presence of a NLS further support this hypothesized function.

Experimental evidence has indicated over 20 interactors with C5orf22. ^[19][20][21] Interactants are localized to both the nucleus and cytoplasm.^[22] The most likely interactors are WBP11, OSM, Surf2, ELOF1, and DDITL4.^[20]

C5orf22 initially appeared in invertebrates approximately 797 million years ago.^[23] It is the only member of its gene family. Human UPF0489 C5orf22 is conserved through invertebrates.^[23] C5orf22 orthologs showed conservation of the two globular domains through bony fish and conservation of 1 globular domain within arthropods.^[12] Isoelectric point and molecular weights of C5orf22 orthologs were within ∓ 0.15 and ∓ 3kDa through bony fish.^[12] There are no paralogs to c5orf22 in humans.^[23]

UPF0489 C5orf22 is slow evolving protein, based on comparisons of the percent corrected divergence of orthologous proteins.^[24]

Recent studies on miRNA's role in breast cancer pathogenesis has correlated upregulation of C5orf22 with reduced survival of breast cancer patients.^[26]

Patient's with tibial muscular dystrophy, exhibit decreased expression of C5orf22. ^[27] Patient's with non-ischemic cardiomyopathy exhibit increased expression of C5orf22.