TRIM16 governs the biogenesis and disposal of stress-induced protein aggregates to evade cytotoxicity: implication for neurodegeneration and cancer

Jena, Kautilya Kumar; Mehto, Subhash; Kolapalli, Srinivasa Prasad; Nath, Parej; Sahu, Rinku; Chauhan, Nishant Ranjan; Sahoo, Pradyumna Kumar; Dhar, Kollori; Das, Saroj Kumar; Chauhan, Swati; Chauhan, Santosh

doi:10.1080/15548627.2019.1586251

Cited by 28 publications

(27 citation statements)

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“…Cancer cells convive with proteotoxic stress by upregulating all the possible mechanisms that are able to maintain proteostasis [ 196 , 197 , 198 , 199 , 200 , 201 , 202 , 203 , 204 ]. As a consequence, cancer cells are more dependent on the presence of HSPs from UPS for their growth and survival [ 205 , 206 ].…”

Section: Proteotoxic Stress In Cancer Cellsmentioning

confidence: 99%

Proteotoxic Stress and Cell Death in Cancer Cells

Brancolini

Iuliano

2020

Cancers

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To maintain proteostasis, cells must integrate information and activities that supervise protein synthesis, protein folding, conformational stability, and also protein degradation. Extrinsic and intrinsic conditions can both impact normal proteostasis, causing the appearance of proteotoxic stress. Initially, proteotoxic stress elicits adaptive responses aimed at restoring proteostasis, allowing cells to survive the stress condition. However, if the proteostasis restoration fails, a permanent and sustained proteotoxic stress can be deleterious, and cell death ensues. Many cancer cells convive with high levels of proteotoxic stress, and this condition could be exploited from a therapeutic perspective. Understanding the cell death pathways engaged by proteotoxic stress is instrumental to better hijack the proliferative fate of cancer cells.

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Section: Proteotoxic Stress In Cancer Cellsmentioning

confidence: 99%

Proteotoxic Stress and Cell Death in Cancer Cells

Brancolini

Iuliano

2020

Cancers

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“…In the latest report by Bellia et al, the UPS activity is reduced in Alzheimer's Disease patients, which is induced by amyloid β peptide that binding to ubiquitin by residues K63 36 . In the other work by Jena et al it is revealed that TRIM16 activates NFE2L2/NRF2 by K63-linked ubiquitination that upregulates the p62 and results in misfolding protein aggregate formation 37 . Thus, we speculated that LLPUC of K63 binding F508del, at least in our system, favors aggregates formation.…”

Section: Discussionmentioning

confidence: 96%

Opposite Regulation of F508del-CFTR Biogenesis by Four Poly-Lysine Ubiquitin Chains

Henri

Yao

et al. 2020

Preprint

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Background: As a misfolding protein, more than 99% of F508del-CFTR (F508del) is degraded by the ubiquitin-proteasome system before its maturation, which results in almost no membrane expression of CFTR and thereby no chloride secretion across epithelial cells of cystic fibrosis patients. The conjugation of ubiquitin chains to the protein substrates is necessary for ubiquitin-mediated proteasomal degradation. Ubiquitin contains seven lysine (K) residues (K6, K11, K27, K29, K33, K48, and K63), all of them can be conjugated one to another forming poly-ubiquitin chains on substrates by mixing together or by only one type of lysine that provides sorting signals for different pathways. Results: Here we report that four lysine linked poly-Ub chains (LLPUCs) were involved in F508del biogenesis: two LLPUCs linked by K11 or K48 of Ub facilitated F508del degradation; whereas the other two linked by K63 and K33 of Ub protected F508del from degradation. LLPUC K11 is more potent for F508del degradation than K48. Moreover, E3 ligase CHIP and RNF5 catalyzed LLPUCs K48 formation and RNF5 also catalyzed LLPUC K11 formation on F508del. Importantly, Those LLPUCs provide F508del with different affinities to the proteasomal shuttle protein (Rad23a) and the proteasomal receptors (Adrm1 and S5a), offering a mechanistic insight of differential regulation F508del different by different LLPUCs. Conclusions: F508del utilizes four specific lysine-linked poly Ub chains and during its biogenesis for opposite destiny through different identification by proteasomal shuttle protein or receptors. These findings provide new insights to understand the CF pathogenesis and are expected to facilitate the development of therapies for this devastating disease.

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“…In addition, TRIM16 is essential for the NRF2/p62-mediated autophagy/aggrephagy activation, promoting protein homeostasis (proteostasis) and cancer cell survival during oxidative/proteotoxic stress (Fig. 3) [85,86]. This action of TRIM16 is required for the protection of HeLa cell apoptosis and death from toxic misfolded proteins in vitro and in vivo [85].…”

Section: Trim11 and Trim16 As Key Links Between Autophagy And Inflammmentioning

confidence: 99%

Crosstalks between inflammasome and autophagy in cancer

et al. 2020

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Both inflammasomes and autophagy have important roles in the intracellular homeostasis, inflammation, and pathology; the dysregulation of these processes is often associated with the pathogenesis of numerous cancers. In addition, they can crosstalk with each other in multifaceted ways to influence various physiological and pathological responses, including cancer. Multiple molecular mechanisms connect the autophagy pathway to inflammasome activation and, through this, may influence the outcome of pro-tumor or anti-tumor responses depending on the cancer types, microenvironment, and the disease stage. In this review, we highlight the rapidly growing literature on the various mechanisms by which autophagy interacts with the inflammasome pathway, to encourage additional applications in the context of tumors. In addition, we provide insight into the mechanisms by which pathogen modulates the autophagy-inflammasome pathway to favor the infection-induced carcinogenesis. We also explore the challenges and opportunities of using multiple small molecules/agents to target the autophagy/inflammasome axis and their effects upon cancer treatment. Finally, we discuss the emerging clinical efforts assessing the potential usefulness of targeting approaches for either autophagy or inflammasome as anticancer strategies, although it remains underexplored in terms of their crosstalks.

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TRIM16 governs the biogenesis and disposal of stress-induced protein aggregates to evade cytotoxicity: implication for neurodegeneration and cancer

Abstract: (2019) TRIM16 governs the biogenesis and disposal of stressinduced protein aggregates to evade cytotoxicity: implication for neurodegeneration and cancer,

Cited by 28 publications

References 1 publication

Proteotoxic Stress and Cell Death in Cancer Cells

Proteotoxic Stress and Cell Death in Cancer Cells

Opposite Regulation of F508del-CFTR Biogenesis by Four Poly-Lysine Ubiquitin Chains

Crosstalks between inflammasome and autophagy in cancer

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