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03

2024

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09

Peng Kesong of Zhejiang University and other teams revealed that TRIM21 inhibits phosphorylation at its Ser403 site and enhances the cytotoxicity of palmitic acid.

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Accumulation and oxidative toxicity of long-chain free fatty acids (FFAs) are a major cause of a variety of pathological conditions. However, the specific mechanism of FFA cytotoxicity is not clear.

On August 22, 2024, Peng Kesong of Zhejiang University and Longitudinal Microstar of New Jersey State University jointly communicated inAutophagy(IF = 14.6) Published online entitled“TRIM21-mediated ubiquitination of SQSTM1/p62 abolishes its Ser403 phosphorylation and enhances palmitic acid cytotoxicity”of research papers.The study found that palmitic acid (PA), the most abundant FFA in blood, can induce phosphorylation and aggregation at Ser403 (S403) of SQSTM1/p62 (isolator 1). These processes capture KEAP1 and activate non-classical SQSTM1-KEAP1-NFE2L2 antioxidant pathways.

Palmitate-induced SQSTM1 S403 phosphorylation and aggregation are dependent on the formation and dimerization of SQSTM1 K7-D69 hydrogen bonds in Phox and Bem 1(PB1) domains, and these changes contribute to the recruitment of TBK1 to phosphorylate the S403 site of SQSTM1.In addition, the ubiquitin E3 ligase TRIM21 performs ubiquitination at the K7 residue of SQSTM1, disrupting the dimerization of PB1, thereby inhibiting S403 phosphorylation and SQSTM1 aggregation. The C92, C111 and C114 sites of TRIM21 are oxidized to form disulfide bonds, leading to their oligomerization and reduced E3 activity. Mutation of these three C residues to S(3CS) prevents oligomerization of TRIM21 and increases its E3 activity. Knocking out TRIM21 results in decreased SQSTM1 K7 ubiquitination, leading to increased SQSTM1 S403 phosphorylation and aggregation, which antagonize palmitic acid-inducedOxidative stressand cytotoxicity play a protective role. Therefore, TRIM21 is a negative regulator of SQSTM1 phosphorylation, aggregation and antioxidant function. TRIM21 has reduced E3 activity after oxidation, thereby contributing to the enhancement of the SQSTM1-KEAP1-NFE2L2 antioxidant pathway.Inhibition of TRIM21 may be an effective strategy for protecting tissues from the lipotoxic effects of long-chain free fatty acids.

The accumulation of intracellular long-chain free fatty acids (FFAs) is closely related to cell dysfunction and plays an important role in the pathogenesis of a variety of diseases, includinginsulin resistancediabetes, cardiovascular disease, inflammation and liver disease. In metabolic dysfunction associated with steatohepatitis (MASH) and fatty liver disease (SLD) patients, serum FFAs levels were elevated. Palmitic acid (PA), the most abundant FFA in circulation, induces cell death in a variety of cell types, including pancreatic beta cells, cardiomyocytes, microvascular endothelial cells, and hepatocytes.PA-induced hepatic lipotoxicity is considered to be one of the factors that play a key role in the pathogenesis of SLD.

At present, various mechanisms have been reported to mediate PA-induced lipotoxicity, including MAPK/JNK-dependent BAX activation, PPP2/PP2A-mediated FOXO3/FoxO3A dephosphorylation, resulting in increased BCL2L11/Bim transcription, increased lysosomal permeability and CTSB (Cathepsin B) activation, endoplasmic reticulum (ER) stress, and reactive oxygen species (ROS) production.Many of these molecular events are interrelated, and ROS are thought to play a major role in FFA lipotoxicity due to impaired intracellular membrane integrity, mitochondrial dysfunction, calcium imbalance, and excessive ER stress.

Among its many functions, the ubiquitin-binding protein SQSTM1/p62 (isolator 1) aggregates specific proteins and delivers themphagosomedegradation, thereby playing a key role in regulating protein homeostasis and redox balance. One of the client proteins isolated by SQSTM1 is KEAP1(Kelch-like ECH-related protein 1), which acts as a negative regulator of antioxidant responses and inhibits the antioxidant transcription factor NFE2L2/Nrf2 (NFE2-like bZIP transcription factor). This sequestering function of SQSTM1 relies on its formation of dimers through hydrogen bonds between lysine (K)7 and aspartate (D)69 residues in the N-terminal Phox and Bem1p(PB1) domains. The authors recently reported that the ubiquitin E3 ligase TRIM21 (tripartite motif containing 21) containing the RING finger domain directly interacts with SQSTM1 and performs ubiquitination at the K7 site through K63-linkage, thereby disrupting K7-D69 hydrogen bonds and inhibiting the oligomerization, aggregation and isolation functions of SQSTM1. TRIM21-mediated ubiquitination of SQSTM1 K7 leads to loss of KEAP1 sequestration and inhibition of antioxidant response.In contrast, TRIM21 deficient cells exhibited increased SQSTM1 oligomerization, protein aggregation, KEAP1 sequestration, NFE2L2 activation, and antioxidant responses.

In addition to the negative regulation of SQSTM1 dimerization and sequestration through K7 ubiquitination, SQSTM1 is regulated at the post-translational level through several other mechanisms.Its sequestration and protein clearance activities are positively regulated by phosphorylation at multiple sites: phosphorylation by casein kinase 2(CK2), TBK1, MAP3K7/TAK1 or ULK1 at SQSTM1 S403 (S405 in mice), phosphorylation by MTORC1 in a dependent manner at S349 (S352 in mice), and phosphorylation by ULK1 at S407 (S409 in mice). Since some of these phosphorylation events are related to the sequestration and antioxidant function of SQSTM1, the molecular relationship between SQSTM1 K7 ubiquitination and these phosphorylation events remains unclear.In the present study, the authors set out to investigate the mechanisms of SQSTM1 aggregation, sequestration, and regulation of its antioxidant capacity under palmitic acid exposure.

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