Coordinated methyl readers: Functional communications in cancer.

Methylation is a major post-translational modification (PTM) generated by methyltransferase on target proteins; it is recognized by the epigenetic reader to expand the functional diversity of proteins. Methylation can occur on specific lysine or arginine residues localized within regulatory domains in both histone and nonhistone proteins, thereby allowing distinguished properties of the targeted protein. Methylated residues are recognized by chromodomain, malignant brain tumor (MBT), Tudor, plant homeodomain (PHD), PWWP, WD-40, ADD, and ankyrin repeats by an induced-fit mechanism. Methylation-dependent activities regulate distinct aspects of target protein function and are largely reliant on methyl readers of histone and nonhistone proteins in various diseases. Methylation of nonhistone proteins that are recognized by methyl readers facilitates the degradation of unwanted proteins, as well as the stabilization of necessary proteins. Unlike nonhistone substrates, which are mainly monomethylated by methyltransferase, histones are di- or trimethylated by the same methyltransferases and then connected to other critical regulators by methyl readers. These fine-tuned controls by methyl readers are significant for the progression or inhibition of diseases, including cancers. Here, current knowledge and our perspectives about regulating protein function by methyl readers are summarized. We also propose that expanded research on the strong crosstalk mechanisms between methylation and other PTMs via methyl readers would augment therapeutic research in cancer.

Regulation of autophagy by protein methylation and acetylation in cancer.

Autophagy is a highly conserved mechanism responsible for cellular homeostasis and integrity in a variety of physiological conditions. Materials targeted for degradation are directed to autophagosomes and autolysosomes, where they are broken down into their base components. Aberrant regulation of autophagy is significantly associated with various cancers and neurodegenerative diseases. Recently, accumulating evidence has revealed that the coordinated regulation of histone and non-histone protein modification is associated with autophagy. In this review, we highlight the recent progress that has been made in elucidating the molecular basis of protein methylation and acetylation associated with autophagy at the transcriptional and posttranslational levels. Furthermore, we discuss the importance of describing causality between protein methylation/acetylation and autophagy regulation as compelling therapeutic opportunities in cancer pathogenesis and progression.

Activation of Lysosomal Function Ameliorates Amyloid-ß-Induced Tight Junction Disruption in the Retinal Pigment Epithelium.

Accumulation of pathogenic amyloid-ß disrupts the tight junction of retinal pigment epithelium (RPE), one of its senescence-like structural alterations. In the clearance of amyloid-ß, the autophagy-lysosome pathway plays the crucial role. In this context, mammalian target of rapamycin (mTOR) inhibits the process of autophagy and lysosomal degradation, acting as a potential therapeutic target for age-associated disorders. However, efficacy of targeting mTOR to treat age-related macular degeneration remains largely elusive. Here, we validated the therapeutic efficacy of the mTOR inhibitors, Torin and PP242, in clearing amyloid-ß by inducing the autophagy-lysosome pathway in a mouse model with pathogenic amyloid-ß with tight junction disruption of RPE, which is evident in dry age-related macular degeneration. High concentration of amyloid-ß oligomers induced autophagy-lysosome pathway impairment accompanied by the accumulation of p62 and decreased lysosomal activity in RPE cells. However, Torin and PP242 treatment restored the lysosomal activity via activation of LAMP2 and facilitated the clearance of amyloid-ß in vitro and in vivo. Furthermore, clearance of amyloid-ß by Torin and PP242 ameliorated the tight junction disruption of RPE in vivo. Overall, our findings suggest mTOR inhibition as a new therapeutic strategy for the restoration of tight junctions in age-related macular degeneration.

Enhancement of phycoerythrin productivity in Porphyridium purpureum using the clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 ribonucleoprotein system.

Genetic manipulation of the Porphyridium sp. may increase the production of phycoerythrin. Since phycobiliproteins capture and transfer energy to both photosystems (PS I and PS II), it was hypothesized that the gene mutation involved increases phycoerythrin synthesis. The gene encoding chlorophyll synthase (CHS1) was selected as chlorophyll synthase plays an important role in photosynthesis, mediating the final process of chlorophyll synthesis. Clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 ribonucleoprotein (CRISPR/Cas9 RNP) delivery system was used to generate the chlorophyll synthase loss-of-function mutants (Δchs1). Independent Δchs1 showed no differences in the growth and production of sulfated polysaccharide compared to control. Phycoerythrin contents of the two independent mutants substantially increased regardless of light source. This study provides a novel applicability for the CRISPR/Cas9 RNP method in red microalgae toward a bio-product of interest. The obtained mutants could serve as potential producers of phycoerythrin if Porphyridium is selected as a natural source.