Nonhistone Lysine Methylation as a Protein Degradation Signal.

Nicholas A Lehning,Brad E Morrison

doi:10.1155/2022/1969299

Abstract

Protein degradation is a fundamental feature of cellular life, and malfunction of this process is implicated in human disease. Ubiquitin tagging is the best characterized mechanism of targeting a protein for degradation; however, there are a growing number of distinct mechanisms which have also been identified that carry out this essential function. For example, covalent tagging of proteins with sequestosome-1 targets them for selective autophagy. Degradation signals are not exclusively polypeptides such as ubiquitin, NEDD8, and sequestosome-1. Phosphorylation, acetylation, and methylation are small covalent additions that can also direct protein degradation. The diversity of substrate sequences and overlap with other pleotrophic functions for these smaller signaling moieties has made their characterization more challenging. However, these small signals might be responsible for orchestrating a large portion of the protein degradation activity in the cell. As such, there has been increasing interest in lysine methylation and associated lysine methyltransferases (KMTs), beyond canonical histone protein modification, in mediating protein degradation in a variety of contexts. This review focuses on the current evidence for lysine methylation as a protein degradation signal with a detailed discussion of the class of enzymes responsible for this phenomenon.

Highlights

Protein degradation is a critical function for regulating signaling and removal of dysfunctional or misfolded proteins. ere are two canonical methods by which this occurs.e ubiquitin/proteasome system (UPS) is the most welldescribed while the second is autophagy, which can be further distinguished as macroautophagy, microautophagy, or chaperone-mediated autophagy. e importance of these processes is illustrated by protein aggregation and other maladies that occur subsequent to the failure of protein turnover machinery
E ubiquitin/proteasome system (UPS) is the most welldescribed while the second is autophagy, which can be further distinguished as macroautophagy, microautophagy, or chaperone-mediated autophagy. e importance of these processes is illustrated by protein aggregation and other maladies that occur subsequent to the failure of protein turnover machinery
As our knowledge base regarding KMTs and lysine methylation expands, so does the breadth of roles this post-translational modification (PTM) plays within the cell

Summary

Introduction

Protein degradation is a critical function for regulating signaling and removal of dysfunctional or misfolded proteins. ere are two canonical methods by which this occurs. Is process, though, requires that the cell target large numbers of proteins for degradation as global proteome turnover occurs. Is dictates a few key requirements that would be necessary for an effective global degradation signal including that it be small and energetically inexpensive, unrestricted by sequence, and paired with an enzyme whose dysfunction is linked to disorders that include aberrant cell differentiation. A number of enzymes exist that have been shown to perform mono-, di-, and trimethylations of lysine residues (Table 1). While most of these enzymes are canonically histone methylators, many of them have overlapping function as nonhistone methylators as well [48]

Methylation of Nonhistone Proteins

Evidence for Lysine Methylation as a Degradation Signal

Summary and Future Perspectives