bims-micpro 2024-08-25 papers

Issue of 2024‒08‒25
five papers selected by
Thomas Farid Martínez, University of California, Irvine

J Proteome Res. 2024 Aug 22.

Proteomic Profiling of Unannotated Microproteins in Human Placenta Reveals XRCC6P1 as a Potential Negative Regulator of Translation.

Qiong Li, Fanrong Liu, Xiaoyu Ma, Feifei Chen, Ziying Yi, Yangyang Du, Anxin Huang, Chenyang Zhao, Da Wang, Yanran Chen, Xiongwen Cao.

Ribosome profiling and mass spectrometry have revealed thousands of previously unannotated small and alternative open reading frames (sm/alt-ORFs) that are translated into micro/alt-proteins in mammalian cells. However, their prevalence across human tissues and biological roles remains largely undefined. The placenta is an ideal model for identifying unannotated microproteins and alt-proteins due to its considerable protein diversity that is required to sustain fetal development during pregnancy. Here, we profiled unannotated microproteins and alt-proteins in human placental tissues from preeclampsia patients or healthy individuals by proteomics, identified 52 unannotated microproteins or alt-proteins, and demonstrated that five microproteins can be translated from overexpression constructs in a heterologous cell line, although several are unstable. We further demonstrated that one microprotein, XRCC6P1, associates with translation initiation factor eIF3 and negatively regulates translation when exogenously overexpressed. Thus, we revealed a hidden sm/alt-ORF-encoded proteome in the human placenta, which may advance the mechanism studies for placenta development as well as placental disorders such as preeclampsia.

Keywords: XRCC6P1; alternative protein; eIF3; human placenta; microprotein; preeclampsia; translation; unannotated protein

DOI: https://doi.org/10.1021/acs.jproteome.4c00319

Plant Biotechnol J. 2024 Aug 20.

Editing and genome-wide analysis upstream open reading frames contributes to enhancing salt tolerance in tomato.

Chunping Jia, Juan Wang, Bin Guo, Tao Yang, Haitao Yang, Baike Wang, Qinghui Yu.

The salinization of soil constitutes a substantial hindrance to the advancement of sustainable agriculture. Our research seeks to elucidate the role of a Rab GTPase-activating protein (RabGAP) family member, SlRabGAP22, in salt tolerance and its translational regulation under salt stress in tomatoes, employing gene-editing techniques and ribosome profiling methodologies. Findings demonstrate that SlRabGAP22 acts as a positive regulator of tomato salt tolerance, with four predicted upstream open reading frames (uORFs) classified into three categories. Functional uORFs were found to be negative regulation. Editing these uORFs along with altering their classifications and characteristics mitigated the inhibitory effects on primary ORFs and fine-tuned gene expression. Enhanced tomato salt tolerance was attributed to improved scavenging of reactive oxygen species, reduced toxicity Na+, and diminished osmotic stress effects. Furthermore, we conducted genome-wide analysis of ORFs to lay the foundation for further research on uORFs in tomatoes. In summary, our findings offer novel perspectives and important data for the enhancement of genetic traits via uORF-based strategies and translational regulation against the backdrop of salt stress.

Keywords: Ribo‐seq; gene editing; salt stress; translational regulation; uORFs

DOI: https://doi.org/10.1111/pbi.14450

Cell. 2024 Aug 16. pii: S0092-8674(24)00802-X. [Epub ahead of print]

Mining human microbiomes reveals an untapped source of peptide antibiotics.

Marcelo D T Torres, Erin F Brooks, Angela Cesaro, Hila Sberro, Matthew O Gill, Cosmos Nicolaou, Ami S Bhatt, Cesar de la Fuente-Nunez.

Drug-resistant bacteria are outpacing traditional antibiotic discovery efforts. Here, we computationally screened 444,054 previously reported putative small protein families from 1,773 human metagenomes for antimicrobial properties, identifying 323 candidates encoded in small open reading frames (smORFs). To test our computational predictions, 78 peptides were synthesized and screened for antimicrobial activity in vitro, with 70.5% displaying antimicrobial activity. As these compounds were different compared with previously reported antimicrobial peptides, we termed them smORF-encoded peptides (SEPs). SEPs killed bacteria by targeting their membrane, synergizing with each other, and modulating gut commensals, indicating a potential role in reconfiguring microbiome communities in addition to counteracting pathogens. The lead candidates were anti-infective in both murine skin abscess and deep thigh infection models. Notably, prevotellin-2 from Prevotella copri presented activity comparable to the commonly used antibiotic polymyxin B. Our report supports the existence of hundreds of antimicrobials in the human microbiome amenable to clinical translation.

Keywords: SEPs; antibiotics; antimicrobial peptides; computational mining; human microbiome; microproteins; peptides; smORF-encoded peptides

DOI: https://doi.org/10.1016/j.cell.2024.07.027

Diabetol Metab Syndr. 2024 Aug 19. 16(1): 200

The correlation between mitochondrial derived peptide (MDP) and metabolic states: a systematic review and meta-analysis.

Qian Zhou, Shao Yin, Xingxing Lei, Yuting Tian, Dajun Lin, Li Wang, Qiu Chen.

BACKGROUND: MOTS-c is known as mitochondrial open reading frame (ORF) of the twelve S c, produced by a small ORF-encoded peptides (SEPs) in mitochondrial 12S rRNA region. There is growing evidence that MOTS-c has a strong relationship with the expression of inflammation- and metabolism-associated genes and metabolic homeostasis, and even offering some protection against insulin resistance (IR). However, studies have reported inconsistent correlations between different population characteristics and MOTS-c levels. This meta-analysis aims to elucidate MOTS-c levels in physiological and pathological states, and its correlation with metabolic features in various physiological states.METHODS: We conducted a systematic review and meta-analysis to synthesize the evidence of changes in blood MOTS-c concentration, and any association between MOTS-c and population characteristic. The Web of Science, PubMed, EMBASE, CNKI, WANGFANG and VIP databases were searched from inception to April 2023. The statistical analysis was summarized using the standardized mean difference (SMD) and 95% confidence interval (95% CIs). Pearson correlation coefficient was used to analyze the correlation and generate forest plots through a random-effects model. Additional analyses as sensitivity and subgroup analyses were performed to identify the origins of heterogeneity. Publication bias was retrieved by means of a funnel-plot analysis and Egger's test. All related statistical analyses were performed using Revman 5.3 and Stata 15 statistical software.
RESULT: There are 6 case-control studies and 1 cross-sectional study (11 groups) including 602 participants in our current meta-analysis. Overall analysis results showed plasma MOTS-c concentration in diabetes and obesity patients was significantly reduced (SMD = - 0.37; 95% CI- 0.53 to - 0.20; P < 0.05). After subgroup analysis, the present analysis has yielded opposite results for MOTS-c changes in obesity (SMD = 0.51; 95% CI 0.21 to 0.81; P < 0.05) and type 2 diabetes mellitus (T2DM) (SMD = - 0.89; 95% CI - 1.12 to - 0.65; P < 0.05) individuals. Moreover, the correlation analysis was performed to identify that MOTS-c levels were significantly positively correlated with TC (r = 0.29, 95% CI 0.20 to 0.38) and LDL-c (r = 0.30, 95% CI 0.22 to 0.39). The subgroup analysis results showed that MOTS-c decreased significantly in patients with diabetes (SMD = - 0.89; 95% CI- 1.12 to - 0.65; P < 0.05). In contrast, the analysis result for obesity persons (BMI > 28 kg/ m2) was statistically significant after overweight people (BMI = 24-28 kg/ m2) were excluded (SMD = 0.51; 95% CI 0.21 to 0.81; P < 0.05), which is completely different from that of diabetes. Publication bias was insignificant (Egger's test: P = 0.722).
CONCLUSION: Circulating MOTS-c level was significantly reduced in diabetic individuals but was increased significantly in obesity patients. The application of monitoring the circulating levels variability of MOTS-c in routine screening for obesity and diabetes is prospects and should be taken into consideration as an important index for the early prediction and prevention of metabolic syndrome in the future. PROSPERO registration number CRD42021248167.

Keywords: Diabetes; Meta-analysis; Mitochondrion; Mots-c; Obesity

DOI: https://doi.org/10.1186/s13098-024-01405-w

Biochim Biophys Acta Mol Cell Res. 2024 Aug 18. pii: S0167-4889(24)00163-0. [Epub ahead of print] 119820

Micropeptide MPM regulates cardiomyocyte proliferation and heart growth via the AKT pathway.

Hua-Xing Chen, Yan-Zhen Ma, Peng-Peng Xie, Jie-Yi Huang, Lan-Qi Li, Wei Zhang, Ying Zhu, Shi-Mei Zhuang, Yi-Fang Lin.

The role of micropeptide in cardiomyocyte proliferation remains unknown. We found that MPM (micropeptide in mitochondria) was highly expressed in cardiomyocytes. Compared to MPM+/+ mice, MPM knockout (MPM-/-) mice exhibited reduction in left ventricular (LV) mass, myocardial thickness and LV fractional shortening. RNA-sequencing analysis in H9c2, a rat cardiomyocyte cell line, identified downregulation of cell cycle-promoting genes as the most significant alteration in MPM-silencing cells. Consistently, gain- and loss-of-function analyses in H9c2 cells revealed that cardiomyocyte proliferation was repressed by silencing MPM but was promoted by overexpressing MPM. Moreover, the cardiomyocytes in the hearts of MPM-/- mice displayed reduced proliferation rates. Mechanism investigations disclosed that MPM is crucial for AKT activation in cardiomyocytes. We also identified an interaction between MPM and PTPMT1, and found that silencing PTPMT1 attenuated the effect of MPM in activating the AKT pathway, whereas inhibition of the AKT pathway abrogated the role of MPM in promoting cardiomyocyte proliferation. Collectively, these results indicate that MPM may promote cardiomyocyte proliferation and thus heart growth by interacting with PTPMT1 to activate the AKT pathway. Our findings identify the novel function and regulatory network of MPM and highlight the importance of micropeptides in cardiomyocyte proliferation and heart growth.

Keywords: AKT pathway; Cardiomyocyte proliferation; MPM; Micropeptide; PTPMT1

DOI: https://doi.org/10.1016/j.bbamcr.2024.119820