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Related Concept Videos

Regulated Protein Degradation02:58

Regulated Protein Degradation

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It is vital to regulate the activity of enzymatic as well as non-enzymatic proteins inside the cell. This can be achieved either through creating a balance between their rate of synthesis and degradation or regulating the intrinsic activity of the protein. Both these regulation mechanisms play an essential role in the normal functioning of cells.
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Eukaryotic cells can degrade proteins through several pathways. One of the most important among these is the ubiquitin-proteasome pathway. It helps the cell eliminate the misfolded, damaged, or unwarranted cytoplasmic proteins in a highly specific manner.
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Regulation of Expression at Multiple Steps01:23

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The gene expression in cells is regulated at different stages: (i) transcription, (ii) RNA processing, (iii) RNA localization, and (iv) translation. Transcriptional regulation is mediated by regulatory proteins such as transcription factors, activators, or repressors—these control gene expression by initiating or inhibiting the transcription of genes. Once a precursor or pre-mRNA is produced, it undergoes post-transcriptional modification, including 5' capping, splicing, and the...
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The ER is the hub of protein synthesis in a cell. It has robust systems to quality control protein folding and also for degradation of terminally misfolded proteins. Under normal conditions, a small proportion of misfolded proteins that cannot be salvaged need to be transported to the cytoplasm by the ER-associated degradation or ERAD pathways. However, if the ERAD cannot handle the misfolded proteins, the cell activates the unfolded protein response or UPR to adjust the protein folding...
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Unlocking LAG3: Ubiquitin's unexpected role.

Ye Zhao1, Kai W Wucherpfennig2

  • 1Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

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Summary

The inhibitory receptor LAG3

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Area of Science:

  • Immunology
  • Molecular Biology
  • Cancer Research

Background:

  • The inhibitory receptor LAG3 (Lymphocyte-Activation Gene 3) plays a role in immune regulation.
  • Understanding LAG3's signaling mechanism is crucial for developing effective cancer immunotherapies.
  • Relatlimab, an FDA-approved monoclonal antibody (mAb), targets LAG3, but its precise mechanism remains unclear.

Purpose of the Study:

  • To elucidate the signaling mechanism of the inhibitory receptor LAG3.
  • To investigate the role of ubiquitination in LAG3's inhibitory function.
  • To identify potential biomarkers for clinical response to LAG3 inhibition.

Main Methods:

  • Co-immunoprecipitation assays to study protein interactions.
  • Western blotting to detect ubiquitination.
  • Analysis of patient data to correlate biomarker expression with clinical response.

Main Results:

  • Ubiquitination of the cytoplasmic domain of LAG3 is essential for its inhibitory function.
  • Co-expression of LAG3 and CBL E3 ligases was identified.
  • This co-expression serves as a biomarker for clinical response to LAG3 inhibition in human melanoma.

Conclusions:

  • Ubiquitination is a key post-translational modification regulating LAG3 inhibitory signaling.
  • LAG3 and CBL E3 ligase co-expression is a predictive biomarker for anti-LAG3 therapy efficacy in melanoma.
  • This finding advances our understanding of LAG3's role in cancer immunity and informs future therapeutic strategies.