Arginine Methylation Modulates Autophagic Degradation of PGL Granules in C. elegans

Abstract

The selective degradation of intracellular components by autophagy involves sequential interactions of the cargo with a receptor, which also binds the autophagosomal protein Atg8 and a scaffold protein. Here, we demonstrated that mutations in C. elegans epg-11, which encodes an arginine methyltransferase homologous to PRMT1, cause the defective removal of PGL-1 and PGL-3 (cargo)-SEPA-1 (receptor) complexes, known as PGL granules, from somatic cells during embryogenesis. Autophagic degradation of the PGL granule scaffold protein EPG-2 and other protein aggregates was unaffected in epg-11/prmt-1 mutants. Loss of epg-11/prmt-1 activity impairs the association of PGL granules with EPG-2 and LGG-1 puncta. EPG-11/PRMT-1 directly methylates arginines in the RGG domains of PGL-1 and PGL-3. Autophagic removal of PGL proteins is impaired when the methylated arginines are mutated. Our study reveals that posttranslational arginine methylation regulates the association of the cargo-receptor complex with the scaffold protein, providing a mechanism for modulating degradation efficiency in selective autophagy.

Protein arginine methyltransferase expression, localization, and activity during disuse-induced skeletal muscle plasticity

“…These adaptations depend on the chronic activation or inhibition of various intracellular signaling pathways, which result in altered skeletal muscle gene expression (2,31). Intracellular signaling molecules such as peroxisome proliferator-activated receptor (PPAR)-γ coactivator-1α (PGC-1α), calcineurin (CN), p38 mitogen-activated protein kinase (p38), AMP-activated protein kinase (AMPK), silent mating type information regulator 2 homologue 1 (SIRT1), PPARβ and tumor suppressor protein p53 play a role in remodelling skeletal muscle toward a slower, more oxidative phenotype (16,18,19,20,21,22,23,24,25). In contrast, receptor interacting protein 140 (RIP140), E2F transcription factor 1 (E2F1), nuclear receptor corepressor 1 (NCoR1), and Baf60c have been shown to promote faster, more glycolytic characteristics (26,27,28,29,32).…”

“…Receptor interacting protein 140 (RIP140), E2F transcription factor 1 (E2F1), nuclear receptor corepressor 1 (NCoR1), and Baf60c and chronic muscle disuse (e.g., denervation, hind limb unloading) promote a faster, more glycolytic phenotype (26,27,28,29). In contrast, chronic activation of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), calcineurin (CN), p38 mitogen-activated protein kinase (p38), AMP-activated protein kinase (AMPK), silent mating type information regulator 2 homologue 1 (SIRT1), PPARβ and tumor suppressor protein p53 by way of transgenic, physiological (e.g., endurance exercise), or pharmacologic (e.g., AICAR) mechanisms foster slower, more oxidative characteristics (16,18,22,24,25). PGC-1α plays a major role in remodelling skeletal muscle due to its ability to translocate to the nucleus and co-activate several transcription factors that bind to promoters of genes indicative of the slow, oxidative myogenic program (16,22,24).…”

“…Recall that FOXO is a powerful driver of the muscle atrophy program via its promotion of the ubiquitin-proteasome and autophagy systems. Furthermore, recent studies have demonstrated that PRMT1 and CARM1 have direct roles in the autophagic signalling pathway (172,179). Although these studies were not performed in skeletal muscle, the data suggest that PRMTs may be important mediators of muscle protein metabolism.…”

PGL germ granule assembly protein is a base-specific, single-stranded RNase

“…By primary sequence prediction, PGLs have only one recognizable region, C-terminal RGG repeats (Fig. 1A) (8,9), which are associated with protein turnover and RNA binding (17,19). In non-PGL proteins, RGG repeats can recruit RNA binding proteins (20) and facilitate in vitro granule formation (21).…”

An asymmetrically dimethylarginated nuclear 90 kDa protein (p90aDMA) induced by interleukin (IL)-2, IL-4 or IL-6 in the tumor microenvironment is selectively degraded by autophagy

“…Mad1, a member of the Myc/Max/Mad family, can also be phosphorylated at serine 145 and introduced into the autophagic degradation (20). Interestingly, EPG-11/ PRMT-1 directly methylates arginines in the RGG domains of PGL-1 and PGL-3 and promotes their autophagic removal in C. elegans during embryogenesis (21). However, the link between arginine methylation and selective autophagy has not been clearly demonstrated in cancer.…”