Summary on The Status Quo and Future Development of Protein Modification Research

Protein post-translational modifications (PTM) include phosphorylation, methylation, acetylation etc. Protein expression is regulated by genomics and epigenetics, and after expression, it needs to be modified to different degrees to perform the required functions. PTM research is crucial. Here, let’s review the significant research in the field of protein modification in 2018.

 

PNAS: Ubiquitin-like protein ubiquilin 2 (UBQLN2) regulates ALS/FTD-linked FUS-RNA complex kinetics and stress granule formation

The ubiquitin-like protein ubiquilin 2 (UBQLN2) is genetically and pathologically associated with neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), but its normal cellular function remains unclear. An article published in the PNAS report found that the enrichment of the UBQLN2 interacting protein stress granules (SG), including ALS/FTD-linked heterologous nuclear ribose protein, fused to sarcoma (FUS).

 

 

With an optimized SG detection method, the researchers observed UBQLN2 and its interactions. The low complexity in UBQLN2, similar to the repeating area of Sti1, is sufficient to locate it in the SG. Functionally, UBQLN2 negatively regulates SG formation. UBQLN2 increases the kinetics of FUS-RNA interactions and promotes the mobility of FUS-RNA complexes at the single molecule level.

 

The results of this study reveal that UBQLN2 provides clues for studying the occurrence of related diseases by directly regulating the fluidity of protein-RNA complexes and the kinetics of SG formation.

 

Science: LZTR1 is a regulator of RAS ubiquitination and signaling

Chronic myeloid leukemia is a malignant tumor that affects blood and bone marrow which is characterized by slow progression and often occurs in people over 50 years of age. A study published in science reports that LZTR1 (the cullin 3 receptor protein encoding leucine zipper-like transcriptional regulator 1) in a genetic screen designed to understand the mechanisms of resistance in chronic myeloid leukemia cells, increases the activity of activated protein kinase pathways and decreases sensitivity to tyrosine kinase inhibitors. The results of this study provide a molecular basis for LZTR1 involvement in a variety of hereditary and acquired human diseases.

 

The studies have shown that in addition to the Drosophila LZTR1, its ortholog CG3711 causes an increase in RAS-dependent functional phenotype. Inactivation of LZTR1 results in reduced ubiquitination and enhanced plasma membrane localization of endogenous KRAS. LZTR1 acts as a conservative regulator of RAS ubiquitination and MAPK pathway activation.

 

EMBO J: The secretory pathway kinase Fam20C regulates the redox homeostasis of the endoplasmic reticulum by phosphorylating the endoplasmic reticulum thiol oxidase Ero1a

The protein kinase Fam20C is the first protein kinase found in the secretory pathway. Fam20C is capable of catalyzing the phosphorylation of more than 100 proteins secreted extracellularly. Its functional defects are closely related to the bone dysplastic disease Rennes syndrome. However, Fam20C has almost a blank on the function of organelles such as endoplasmic reticulum.

 

In an article published in EMBO J, the researchers first discovered that Fam20C interacts with 349 proteins localized to the endoplasmic reticulum and Golgi through interacting proteomics, and many key enzymes in the protein folding pathway are highly enriched. Further studies afterward revealed that the secretory pathway kinase Fam20C regulates the redox homeostasis of the endoplasmic reticulum by phosphorylating the endoplasmic reticulum thiol oxidase Ero1a.

 

 

This study established a link between phosphorylation of proteins and oxidative folding for the first time. It provided a new mechanism for the regulation of the environment and function of endocrine networks and other secretory pathways, also revealing a new biological function of protein phosphorylation.

 

Cell Rep: CSAP is a TTLL-mediated regulator of microtubule glutamination

Tubulin glutamylation is a reversible post-translational modification that accumulates on stable microtubules (MT). Abnormally high levels of this modification result in many diseases such as male sterility, retinal degeneration, and neurodegeneration, however, researchers know very little about the molecular mechanisms by which glutamylase activity is regulated. An article published in Cell Rep reports that CSAP is a TTLL-mediated regulator of microtubule glutamination.

 

The researchers found that CSAP forms a complex with TTLL5 and demonstrates that these two proteins mutually regulate their mutual abundance. Studies have also shown that CSAP increases TTLL5-mediated glutamylation and recognizes the TTLL5 interaction domain, losing this domain will result in a complete loss of CSAP activation functionality, but will not affect its MT binding. The combination of CSAP and TTLL5 facilitates the relocation of TTLL5 to MT. Finally, the authors claim that CSAP binds and activates all remaining autonomously active TTLL glutamylase.

 

Cell Rep: SIRT1 controls centrosome replication by temporarily adjusting the Plk2 level

The centrosome is a key regulator of cell cycle progression and genomic stability. Studies have shown that SIRT1 (Sirtuin 1) regulates many cellular processes, including cell cycle progression, DNA damage response, and metabolism, but the association between the two remains poorly understood. An article published in Cell Rep reports that acetylation protects Plk2 from ubiquitination and SIRT1-mediated deacetylation promotes ubiquitin-dependent degradation of Plk2. This study revealed the key role of SIRT1 in centrosome replication.

 

Studies have shown that SIRT1 controls centrosome replication by temporarily regulating centrosome Plk2 levels. AURKA phosphorylates SIRT1 and promotes SIRT1-Plk2 interactions in mitosis. In the early and middle stages of G1, phosphorylated SIRT1 deacetylates and promotes Plk2 degradation. In the late G1, SIRT1 is dephosphorylated and its affinity for Plk2 is reduced, resulting in rapid accumulation of centrosome Plk2, triggering centrosome replication.

 

Protein modification has great significance for the fine regulation of physiological activities. Protein modification makes the structure of protein more complex and diverse, and its function is more clear and fine. In addition, the optimization of therapeutic protein efficacy can also be achieved by chemical modification in various ways which confirm there are more researches needed for the future of protein modification research.

 

 

 

Reference

[1] Alexander EJ, et al. Ubiquilin 2 modulates ALS/FTD-linked FUS-RNA complex dynamics and stress granule formation[J]. Proc Natl Acad Sci U S A, 2018.

[2] Bigenzahn JW, et al. LZTR1 is a regulator of RAS ubiquitination and signaling [J]. Science, 2018.

[3] Zhang J, et al. Secretory kinase Fam20C tunes endoplasmic reticulum redox state via phosphorylation of Ero1α [J]. EMBO J, 2018.

[4] Bompard G et al. CSAP Acts as a Regulator of TTLL-Mediated Microtubule Glutamylation [J]. Cell Rep, 2018.

[5] Ling H, et al. Histone Deacetylase SIRT1 Targets Plk2 to Regulate Centriole Duplication [J]. Cell Rep, 2018.

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