bims-micpro 2022-08-21 papers

Cell Rep. 2022 Aug 16. pii: S2211-1247(22)01021-X. [Epub ahead of print]40(7): 111204

Mitochondrial microproteins link metabolic cues to respiratory chain biogenesis.

Chao Liang, Shan Zhang, David Robinson, Matthew Vander Ploeg, Rebecca Wilson, Jiemin Nah, Dale Taylor, Sheryl Beh, Radiance Lim, Lei Sun, Deborah M Muoio, David A Stroud, Lena Ho.

Electron transport chain (ETC) biogenesis is tightly coupled to energy levels and availability of ETC subunits. Complex III (CIII), controlling ubiquinol:ubiquinone ratio in ETC, is an attractive node for modulating ETC levels during metabolic stress. Here, we report the discovery of mammalian Co-ordinator of mitochondrial CYTB (COM) complexes that regulate the stepwise CIII biogenesis in response to nutrient and nuclear-encoded ETC subunit availability. The COMA complex, consisting of UQCC1/2 and membrane anchor C16ORF91, facilitates translation of CIII enzymatic core subunit CYTB. Subsequently, microproteins SMIM4 and BRAWNIN together with COMA subunits form the COMB complex to stabilize nascent CYTB. Finally, UQCC3-containing COMC facilitates CYTB hemylation and association with downstream CIII subunits. Furthermore, when nuclear CIII subunits are limiting, COMB is required to chaperone nascent CYTB to prevent OXPHOS collapse. Our studies highlight CYTB synthesis as a key regulatory node of ETC biogenesis and uncover the roles of microproteins in maintaining mitochondrial homeostasis.

Keywords: CP: Metabolism; CYTB; SEPs; SMIM4; UQCC1; UQCC2; complex III; electron transport chain; microproteins; nuclear-mitochondrial coordination; smORFs

DOI: https://doi.org/10.1016/j.celrep.2022.111204

Cell Biosci. 2022 Aug 14. 12(1): 130

OpenVar: functional annotation of variants in non-canonical open reading frames.

Marie A Brunet, Sébastien Leblanc, Xavier Roucou.

BACKGROUND: Recent technological advances have revealed thousands of functional open reading frames (ORF) that have eluded reference genome annotations. These overlooked ORFs are found throughout the genome, in any reading frame of transcripts, mature or non-coding, and can overlap annotated ORFs in a different reading frame. The exploration of these novel ORFs in genomic datasets and of their role in genetic traits is hindered by a lack of software.
RESULTS: Here, we present OpenVar, a genomic variant annotator that mends that gap and fosters meaningful discoveries. To illustrate the potential of OpenVar, we analysed all variants within SynMicDB, a database of cancer-associated synonymous mutations. By including non-canonical ORFs in the analysis, OpenVar yields a 33.6-fold, 13.8-fold and 8.3-fold increase in high impact variants over Annovar, SnpEff and VEP respectively. We highlighted an overlapping non-canonical ORF in the HEY2 gene where variants significantly clustered.
CONCLUSIONS: OpenVar integrates non-canonical ORFs in the analysis of genomic variants, unveiling new research avenues to better understand the genotype-phenotype relationships.

Keywords: Alternative ORF; Genome; NGS; OpenProt; SNP; Small ORF; Variant annotation

DOI: https://doi.org/10.1186/s13578-022-00871-x

Trends Immunol. 2022 Aug 11. pii: S1471-4906(22)00142-9. [Epub ahead of print]

Short open reading frame genes in innate immunity: from discovery to characterization.

Eric Malekos, Susan Carpenter.

Next-generation sequencing (NGS) technologies have greatly expanded the size of the known transcriptome. Many newly discovered transcripts are classified as long noncoding RNAs (lncRNAs) which are assumed to affect phenotype through sequence and structure and not via translated protein products despite the vast majority of them harboring short open reading frames (sORFs). Recent advances have demonstrated that the noncoding designation is incorrect in many cases and that sORF-encoded peptides (SEPs) translated from these transcripts are important contributors to diverse biological processes. Interest in SEPs is at an early stage and there is evidence for the existence of thousands of SEPs that are yet unstudied. We hope to pique interest in investigating this unexplored proteome by providing a discussion of SEP characterization generally and describing specific discoveries in innate immunity.

Keywords: Bifunctional genes; Innate immunity; Short open reading frames (sORFs)

DOI: https://doi.org/10.1016/j.it.2022.07.005