Pathogenic signal peptide variants in the human genome.

Secreted and membrane proteins represent a third of all cellular proteins and contain N-terminal signal peptides that are required for protein targeting to endoplasmic reticulum (ER). Mutations in signal peptides affect protein targeting, translocation, processing, and stability, and are associated with human diseases. However, only a few of them have been identified or characterized. In this report, we identified pathogenic signal peptide variants across the human genome using bioinformatic analyses and predicted the molecular mechanisms of their pathology. We recovered more than 65 thousand signal peptide mutations, over 11 thousand we classified as pathogenic, and proposed framework for distinction of their molecular mechanisms. The pathogenic mutations affect over 3.3 thousand genes coding for secreted and membrane proteins. Most pathogenic mutations alter the signal peptide hydrophobic core, a critical recognition region for the signal recognition particle, potentially activating the Regulation of Aberrant Protein Production (RAPP) quality control and specific mRNA degradation. The remaining pathogenic variants (about 25%) alter either the N-terminal region or signal peptidase processing site that can result in translocation deficiencies at the ER membrane or inhibit protein processing. This work provides a conceptual framework for the identification of mutations across the genome and their connection with human disease.

Ribosome Specialization in Protozoa Parasites.

Ribosomes, in general, are viewed as constitutive macromolecular machines where protein synthesis takes place; however, this view has been recently challenged, supporting the hypothesis of ribosome specialization and opening a completely new field of research. Recent studies have demonstrated that ribosomes are heterogenous in their nature and can provide another layer of gene expression control by regulating translation. Heterogeneities in ribosomal RNA and ribosomal proteins that compose them favor the selective translation of different sub-pools of mRNAs and functional specialization. In recent years, the heterogeneity and specialization of ribosomes have been widely reported in different eukaryotic study models; however, few reports on this topic have been made on protozoa and even less on protozoa parasites of medical importance. This review analyzes heterogeneities of ribosomes in protozoa parasites highlighting the specialization in their functions and their importance in parasitism, in the transition between stages in their life cycle, in the change of host and in response to environmental conditions.

Specialized Ribosomes in Health and Disease.

Ribosomal heterogeneity exists within cells and between different cell types, at specific developmental stages, and occurs in response to environmental stimuli. Mounting evidence supports the existence of specialized ribosomes, or specific changes to the ribosome that regulate the translation of a specific group of transcripts. These alterations have been shown to affect the affinity of ribosomes for certain mRNAs or change the cotranslational folding of nascent polypeptides at the exit tunnel. The identification of specialized ribosomes requires evidence of the incorporation of different ribosomal proteins or of modifications to rRNA and/or protein that lead(s) to physiologically relevant changes in translation. In this review, we summarize ribosomal heterogeneity and specialization in mammals and discuss their relevance to several human diseases.

Defective Human SRP Induces Protein Quality Control and Triggers Stress Response.

Regulation of Aberrant Protein Production (RAPP) is a protein quality control in mammalian cells. RAPP degrades mRNAs of nascent proteins not able to associate with their natural interacting partners during synthesis at the ribosome. However, little is known about the molecular mechanism of the pathway, its substrates, or its specificity. The Signal Recognition Particle (SRP) is the first interacting partner for secretory proteins. It recognizes signal sequences of the nascent polypeptides when they are exposed from the ribosomal exit tunnel. Here, we reveal the generality of the RAPP pathway on the whole transcriptome level through depletion of human SRP54, an SRP subunit. This depletion triggers RAPP and leads to decreased expression of the mRNAs encoding a number of secretory and membrane proteins. The loss of SRP54 also leads to the dramatic upregulation of a specific network of HSP70/40/90 chaperones (HSPA1A, DNAJB1, HSP90AA1, and others), increased ribosome associated ubiquitination, and change in expression of RPS27 and RPS27L suggesting ribosome rearrangement. These results demonstrate the complex nature of defects in protein trafficking, mRNA and protein quality control, and provide better understanding of their mechanisms at the ribosome.

Signal Recognition Particle in Human Diseases.

The signal recognition particle (SRP) is a ribonucleoprotein complex with dual functions. It co-translationally targets proteins with a signal sequence to the endoplasmic reticulum (ER) and protects their mRNA from degradation. If SRP is depleted or cannot recognize the signal sequence, then the Regulation of Aberrant Protein Production (RAPP) is activated, which results in the loss of secretory protein mRNA. If SRP recognizes the substrates but is unable to target them to ER, they may mislocalize or degrade. All these events lead to dramatic consequence for protein biogenesis, activating protein quality control pathways, and creating pressure on cell physiology, and might lead to the pathogenesis of disease. Indeed, SRP dysfunction is involved in many different human diseases, including: congenital neutropenia; idiopathic inflammatory myopathy; viral, protozoal, and prion infections; and cancer. In this work, we analyze diseases caused by SRP failure and discuss their possible molecular mechanisms.

SRPassing Co-translational Targeting: The Role of the Signal Recognition Particle in Protein Targeting and mRNA Protection.

Signal recognition particle (SRP) is an RNA and protein complex that exists in all domains of life. It consists of one protein and one noncoding RNA in some bacteria. It is more complex in eukaryotes and consists of six proteins and one noncoding RNA in mammals. In the eukaryotic cytoplasm, SRP co-translationally targets proteins to the endoplasmic reticulum and prevents misfolding and aggregation of the secretory proteins in the cytoplasm. It was demonstrated recently that SRP also possesses an earlier unknown function, the protection of mRNAs of secretory proteins from degradation. In this review, we analyze the progress in studies of SRPs from different organisms, SRP biogenesis, its structure, and function in protein targeting and mRNA protection.