bims-micpro 2020-11-29 papers

Issue of 2020‒11‒29
two papers selected by
Thomas Martinez
Salk Institute for Biological Studies

Trends Biochem Sci. 2020 Nov 24. pii: S0968-0004(20)30265-6. [Epub ahead of print]

Tristan Cardon, Isabelle Fournier, Michel Salzet.

Conventionally, eukaryotic mRNAs were thought to be monocistronic, leading to the translation of a single protein. However, large-scale proteomics has led to the identification of proteins translated from alternative open reading frames (AltORFs) in mRNAs. AltORFs are found in addition to predicted reference ORFs and noncoding RNA. Alternative proteins are not represented in the conventional protein databases, and this 'Ghost proteome' was not considered until recently. Some of these proteins are functional, and there is growing evidence that they are involved in central functions in physiological and physiopathological contexts. Here, we review how this Ghost proteome fills the gap in our understanding of signaling pathways, establishes new markers of pathologies, and highlights therapeutic targets.

Keywords: SEPs; alternative protein (AltProt); hidden proteome; mass spectrometry; smProt; small ORF (smORF)

DOI: https://doi.org/10.1016/j.tibs.2020.10.003

EMBO Rep. 2020 Nov 23. e50640

The FUS gene is dual-coding with both proteins contributing to FUS-mediated toxicity.

Marie A Brunet, Jean-Francois Jacques, Sonya Nassari, Giulia E Tyzack, Philip McGoldrick, Lorne Zinman, Steve Jean, Janice Robertson, Rickie Patani, Xavier Roucou.

Novel functional coding sequences (altORFs) are camouflaged within annotated ones (CDS) in a different reading frame. We show here that an altORF is nested in the FUS CDS, encoding a conserved 170 amino acid protein, altFUS. AltFUS is endogenously expressed in human tissues, notably in the motor cortex and motor neurons. Over-expression of wild-type FUS and/or amyotrophic lateral sclerosis-linked FUS mutants is known to trigger toxic mechanisms in different models. These include inhibition of autophagy, loss of mitochondrial potential and accumulation of cytoplasmic aggregates. We find that altFUS, not FUS, is responsible for the inhibition of autophagy, and pivotal in mitochondrial potential loss and accumulation of cytoplasmic aggregates. Suppression of altFUS expression in a Drosophila model of FUS-related toxicity protects against neurodegeneration. Some mutations found in ALS patients are overlooked because of their synonymous effect on the FUS protein. Yet, we show they exert a deleterious effect causing missense mutations in the overlapping altFUS protein. These findings demonstrate that FUS is a bicistronic gene and suggests that both proteins, FUS and altFUS, cooperate in toxic mechanisms.

Keywords: FUS; alternative ORF; amyotrophic lateral sclerosis; dual coding; polycistronic

DOI: https://doi.org/10.15252/embr.202050640