TRIM16 controls turnover of protein aggregates by modulating NRF2, ubiquitin system, and autophagy: implication for tumorigenesis

Jena, Kautilya Kumar; Kolapalli, Srinivasa Prasad; Mehto, Subhash; Chauhan, Swati; Chauhan, Santosh

doi:10.1080/23723556.2018.1532251

Cited by 8 publications

(7 citation statements)

References 10 publications

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“…Several TRIM proteins have been shown to modulate the selective autophagy process (Chauhan et al, 2016;Fusco et al, 2018;Jena et al, 2018;Kimura et al, 2015Kimura et al, , 2016Mandell et al, 2014), and during the completion of this paper Di Rienzo and co-workers (2019) identified TRIM32 as a regulator of ULK1 activity in atrophic muscle cells. Similarly to ULK1, p62 activity during selective autophagy is regulated by ubiquitylation.…”

Section: Discussionmentioning

confidence: 94%

TRIM32, but not its muscular dystrophy-associated mutant, positively regulates and is targeted to autophagic degradation by p62/SQSTM1

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Garcia-Garcia

Bhujabal

et al. 2019

Journal of Cell Science

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The tripartite motif (TRIM) proteins constitute a family of ubiquitin E3 ligases involved in a multitude of cellular processes, including protein homeostasis and autophagy. TRIM32 is characterized by six protein-protein interaction domains termed NHL, various point mutations in which are associated with limb-girdle-muscular dystrophy 2H (LGMD2H). Here, we show that TRIM32 is an autophagy substrate. Lysosomal degradation of TRIM32 was dependent on ATG7 and blocked by knockout of the five autophagy receptors p62 (also known as SQSTM1), NBR1, NDP52 (also known as CALCOCO2), TAX1BP1 and OPTN, pointing towards degradation by selective autophagy. p62 directed TRIM32 to lysosomal degradation, while TRIM32 mono-ubiquitylated p62 on lysine residues involved in regulation of p62 activity. Loss of TRIM32 impaired p62 sequestration, while reintroduction of TRIM32 facilitated p62 dot formation and its autophagic degradation. A TRIM32 LGMD2H disease mutant was unable to undergo autophagic degradation and to mono-ubiquitylate p62, and its reintroduction into the TRIM32knockout cells did not affect p62 dot formation. In light of the important roles of autophagy and p62 in muscle cell proteostasis, our results point towards impaired TRIM32-mediated regulation of p62 activity as a pathological mechanisms in LGMD2H.

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Section: Discussionmentioning

confidence: 94%

TRIM32, but not its muscular dystrophy-associated mutant, positively regulates and is targeted to autophagic degradation by p62/SQSTM1

Overå

Garcia-Garcia

Bhujabal

et al. 2019

Journal of Cell Science

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“…MAPT protein can be ubiquitinated, and the ubiquitination of MAPT can increase its aggregation [ 20 ]. Additionally, ubiquitin can also be recruited to mutant huntingtin aggregates [ 21 ]. Ubiquitination of the N-terminus of HTT is found to affect aggregation [ 22 ].…”

Section: Resultsmentioning

confidence: 99%

“…TRIM16, another member of TRIM family, could stabilize and active NFE2L2 to govern the process of protein aggregates degradation [ 21 ]. Hence, we test whether TRIM44 could assess any potential role in the SQSTM1-KEAP1-NFE2L2 complex activating autophagy.…”

Section: Resultsmentioning

confidence: 99%

TRIM44 links the UPS to SQSTM1/p62-dependent aggrephagy and removing misfolded proteins

2021

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Until recently, the ubiquitin-proteasome system (UPS) and macroautophagy/autophagy were considered to be two independent systems that target proteins for degradation by proteasomes or via lysosomes, respectively. Here, we report that TRIM44 (tripartite motif containing 44) is a novel link that connects the UPS system with the autophagy degradation pathway. Suppressing the UPS degradation pathway leads to TRIM44 upregulation, which further promotes aggregated protein clearance through the binding of K48 ubiquitin chains on proteins. TRIM44 expression activates autophagy via promoting SQSTM1/p62 oligomerization, which rapidly increases the rate of aggregate protein removal. Overall, our data reveal that TRIM44 is a newly identified link between the UPS system and the autophagy pathway. Delineating the cross-talk between these two degradation pathways may reveal new mechanisms of targeting aggregate-prone diseases, such as cancer and neurodegenerative disease.

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“…Additionally, autophagy selectively targets membraneless organelles such as stress granules and lipid droplets (lipophagy) [5,6]. Further, several kinds of protein aggregates that could be harmful to the cells are selectively cleared by autophagy (aggrephagy) [7,8] (Fig. 1).…”

Section: Autophagy: Cargoes and Selectivitymentioning

confidence: 99%

Innate immunity and inflammophagy: balancing the defence and immune homeostasis

et al. 2021

Self Cite

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Extensive crosstalk exists between autophagy and innate immune signalling pathways. The stimuli that induce pattern recognition receptor (PRR)mediated innate immune signalling pathways, also upregulate autophagy. The purpose of this increased autophagy is to eliminate the stimuli and/or suppress the inflammatory pathways by targeted degradation of PRRs or intermediary proteins (termed 'inflammophagy'). By executing these functions, autophagy dampens excess inflammation triggered by the innate immune signalling pathways. Thus, autophagy helps in the maintenance of the body's innate immune homeostasis to protect from inflammatory and autoimmune diseases. Many autophagy-dependent mechanisms that could control innate immune signalling have been studied over the last few years. However, still, the understanding is incomplete, and studies that are more systematic should be undertaken to delineate the mechanisms of inflammophagy. Here, we discuss the available knowledge of crosstalk between autophagy and PRR signalling pathways.

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TRIM16 controls turnover of protein aggregates by modulating NRF2, ubiquitin system, and autophagy: implication for tumorigenesis

Cited by 8 publications

References 10 publications

TRIM32, but not its muscular dystrophy-associated mutant, positively regulates and is targeted to autophagic degradation by p62/SQSTM1

TRIM32, but not its muscular dystrophy-associated mutant, positively regulates and is targeted to autophagic degradation by p62/SQSTM1

TRIM44 links the UPS to SQSTM1/p62-dependent aggrephagy and removing misfolded proteins

Innate immunity and inflammophagy: balancing the defence and immune homeostasis

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