bims-micpro 2023-09-24 papers

Cell Rep. 2023 Sep 18. pii: S2211-1247(23)01157-9. [Epub ahead of print]42(9): 113145

Unannotated microprotein EMBOW regulates the interactome and chromatin and mitotic functions of WDR5.

Yanran Chen, Haomiao Su, Jianing Zhao, Zhenkun Na, Kevin Jiang, Antonella Bacchiocchi, Ken H Loh, Ruth Halaban, Zhentian Wang, Xiongwen Cao, Sarah A Slavoff.

The conserved WD40-repeat protein WDR5 interacts with multiple proteins both inside and outside the nucleus. However, it is currently unclear whether and how the distribution of WDR5 between complexes is regulated. Here, we show that an unannotated microprotein EMBOW (endogenous microprotein binder of WDR5) dually encoded in the human SCRIB gene interacts with WDR5 and regulates its binding to multiple interaction partners, including KMT2A and KIF2A. EMBOW is cell cycle regulated, with two expression maxima at late G1 phase and G2/M phase. Loss of EMBOW decreases WDR5 interaction with KIF2A, aberrantly shortens mitotic spindle length, prolongs G2/M phase, and delays cell proliferation. In contrast, loss of EMBOW increases WDR5 interaction with KMT2A, leading to WDR5 binding to off-target genes, erroneously increasing H3K4me3 levels, and activating transcription of these genes. Together, these results implicate EMBOW as a regulator of WDR5 that regulates its interactions and prevents its off-target binding in multiple contexts.

Keywords: CP: Cell biology; CP: Molecular biology; WDR5; histone H3K4me3; microprotein; mitosis; transcription

DOI: https://doi.org/10.1016/j.celrep.2023.113145

J Chem Inf Model. 2023 Sep 21.

miPEPPred-FRL: A Novel Method for Predicting Plant MiRNA-Encoded Peptides Using Adaptive Feature Representation Learning.

Haibin Li, Jun Meng, Zhaowei Wang, Youwei Tang, Shihao Xia, Yu Wang, Zhaojing Qin, Yushi Luan.

MicroRNAs (miRNAs) are an essential type of small molecule RNAs that play significant regulatory roles in organisms. Recent studies have demonstrated that small open reading frames (sORFs) harbored in primary miRNAs (pri-miRNAs) can encode small peptides, known as miPEPs. Plant miPEPs can increase the abundance and activity of cognate miRNAs by promoting the transcription of their corresponding pri-miRNAs, thereby modulating plant traits. Biological experiments are the most effective way to accurately identify miPEPs; however, they are time-consuming and expensive. Hence, an efficient computational method for the identification of miPEPs on a large scale is highly desirable. Up to now, there have been no specialized computational tools for identifying miPEPs. In this work, a novel predictor named miPEPPred-FRL based on an adaptive feature representation learning framework that consists of the feature transformation module and the cascade architecture has been proposed. The feature transformation module integrating a newly designed feature selection method and classifier selection rule is developed to convert sequence-based features into primary class and probabilistic features, which are then fed into the improved cascade architecture to obtain more stable and discriminative augmented features. Finally, the augmented features are utilized to construct the final predictor. Cross-validation experiments illustrate that the novel feature selection method and classifier selection rule contribute to boosting the feature representation ability of the framework. Furthermore, the high accuracy of miPEPPred-FRL on independent testing data suggests that it is a trustworthy and valuable tool for the identification of miPEPs.

DOI: https://doi.org/10.1021/acs.jcim.3c01020

Cell Mol Life Sci. 2023 Sep 16. 80(10): 293

Plant-derived cell-penetrating microprotein α-astratide aM1 targets Akt signaling and alleviates insulin resistance.

Bamaprasad Dutta, Shining Loo, Antony Kam, James P Tam.

Insulin-resistant diabetes is a common metabolic disease with serious complications. Treatments directly addressing the underlying molecular mechanisms involving insulin resistance would be desirable. Our laboratory recently identified a proteolytic-resistant cystine-dense microprotein from huáng qí (Astragalus membranaceus) called α-astratide aM1, which shares high sequence homology to leginsulins. Here we show that aM1 is a cell-penetrating insulin mimetic, enters cells by endocytosis, and activates the PI3K/Akt signaling pathway independent of the insulin receptor leading to translocation of glucose transporter GLUT4 to the cell surface to promote glucose uptake. We also showed that aM1 alters gene expression, suppresses lipid synthesis and uptake, and inhibits intracellular lipid accumulation in myotubes and adipocytes. By reducing intracellular lipid accumulation and preventing lipid-induced, PKCθ-mediated degradation of IRS1/2, aM1 restores glucose uptake to overcome insulin resistance. These findings highlight the potential of aM1 as a lead for developing orally bioavailable insulin mimetics to expand options for treating diabetes.

Keywords: Cell penetration; Cholesterol biosynthesis; Diabetes; Glucose uptake; IRS1/2; Insulin resistance; Insulin-mimetic; Leginsulin; Microproteins; PI3K/Akt signaling; PKCθ; α-Astratide

DOI: https://doi.org/10.1007/s00018-023-04937-y