Coordinate regulation of the senescent state by selective autophagy

Lee, Yeonghyeon; Kim, Jae‐Jin; Kim, Mi Sung; Yoojin, Kwon; Shin, Sanghee; Yi, Hyerim; Kim, Hyeonkyeong; Chang, Moon Jong; Chang, Chong Bum; Kang, Sungchul; Kim, V. Narry; Kim, Jin Hong; Kim, Jong Seo; Elledge, Stephen J.; Kang, Chanhee

doi:10.1016/j.devcel.2021.04.008

Cited by 40 publications

(33 citation statements)

References 76 publications

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“…In particular, RAB11FIP5, the autophagy receptors TAX1BP1 and OPTN as well as the ULK1 complex component RB1CC1 (FIP200) were the most abundant HCIPs. Consistent with previous reports 11 , we observed that the TNIP1-OPTN interaction occurs via the ∆AHD4 domain by IP/MS and IP/immunoblotting (Figure 4 A,B). Interestingly, we also confirmed binding of TNIP1 to TAX1BP1 12 , which we found to require the AHD3 domain, suggesting that TNIP1's function in mitophagy might depend on TAX1BP1.…”

Section: Tnip1 Is a Negative Regulator Of Mitophagysupporting

confidence: 93%

TNIP1 inhibits Mitophagy via interaction with FIP200 and TAX1BP1

Guerroué

Werner

Wang

et al. 2022

Preprint

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Mitophagy is a form of selective autophagy that disposes of superfluous and potentially damage-inducing organelles in a tightly controlled manner. While the machinery involved in mitophagy induction is well known, the regulation of the components is less clear. For example, it is still unknown how the ULK1 complex is dissociated prior to closing of the autophagosome. Here, using Chemically Inducible Dimerization (CID) and mitophagy assays with the fluorescent probe mtKeima, we reveal that the ubiquitin binding domain-containing protein TNIP1 is able to induce mitophagy when ectopically targeted to mitochondria. Conversely, we demonstrate that TNIP1 knock down accelerates mitophagy rates, and that ectopic TNIP1 negatively regulates the rate of mitophagy. These functions of TNIP1 depend on a previously unrecognized, evolutionarily conserved LIR motif as well as its AHD3 domain, which are required for binding to the ULK1 complex member FIP200 and the autophagy receptor TAX1BP1, respectively. Taken together, our findings identify a novel negative regulator of mitophagy that acts at the early steps of autophagosome biogenesis and provide a molecular rationale for how the ULK1 complex might be dissociated from the closing autophagosome.

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Section: Tnip1 Is a Negative Regulator Of Mitophagysupporting

confidence: 93%

TNIP1 inhibits Mitophagy via interaction with FIP200 and TAX1BP1

Guerroué

Werner

Wang

et al. 2022

Preprint

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“…In particular, the selective autophagy of Keap1, the cytoplasmic inhibitor of Nrf2, promoted redox homeostasis during senescence. Interestingly, these selective autophagy networks are clearly observed in vivo in human osteoarthritis [ 60 ].…”

Section: Discussionmentioning

confidence: 99%

Biochemical and Cellular Characterization of New Radio-Resistant Cell Lines Reveals a Role of Natural Flavonoids to Bypass Senescence

Russo¹,

Spagnuolo²,

Moccia³

et al. 2021

IJMS

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Cancer is one of the main causes of death worldwide, and, among the most frequent cancer types, osteosarcoma accounts for 56% of bone neoplasms observed in children and colorectal cancer for 10.2% of tumors diagnosed in the adult population. A common and frequent hurdle in cancer treatment is the emergence of resistance to chemo- and radiotherapy whose biological causes are largely unknown. In the present work, human osteosarcoma (SAOS) and colorectal adenocarcinoma (HT29) cell lines were γ-irradiated at doses mimicking the sub-lethal irradiation in clinical settings to obtain two radio-resistant cellular sub-populations named SAOS400 and HT500, respectively. Since “therapy-induced senescence” (TIS) is often associated with tumor response to radiotherapy in cancer cells, we measured specific cellular and biochemical markers of senescence in SAOS400 and HT500 cells. In detail, both cell lines were characterized by a higher level of expression of cyclin-dependent kinase inhibitors p16INK4 and p21CIP1 and increased positivity to SAβ-gal (senescence-associated β-galactosidase) with respect to parental cells. Moreover, the intracellular levels of reactive oxygen species in the resistant cells were significantly lower compared to the parental counterparts. Subsequently, we demonstrated that senolytic agents were able to sensitize SAOS400 and HT500 to cell death induced by γ-irradiation. Employing two natural flavonoids, fisetin and quercetin, and a BH3-mimetic, ABT-263/navitoclax, we observed that their association with γ-irradiation significantly reduced the expression of p16INK4, p21CIP1 and synergistically (combination index < 1) increased cell death compared to radiation mono-alone treatments. The present results reinforce the potential role of senolytics as adjuvant agents in cancer therapy.

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“…It should be mentioned that the literature regarding the relationship between autophagy and senescence is still inconclusive, with some reports suggesting that autophagy suppresses cellular senescence by removing damaged macromolecules or organelles, and others indicating that autophagy promotes cellular senescence by facilitating the synthesis of senescence-associated secretory phenotype molecules [ 68 , 69 ]. A recent study provided a possible explanation for this apparent discrepancy: the basic autophagic response has a well-established antisenescence role by eliminating damaged macromolecules/organelles that could induce the senescent phenotype, while selective autophagy of multiple regulatory components that are involved in several senescence-related processes explains its prosenescent function [ 70 ]. Our data here add novel elements to the further elucidation of this proposal.…”

Section: Discussionmentioning

confidence: 99%

Dysregulation of Caveolin-1 Phosphorylation and Nuclear Translocation Is Associated with Senescence Onset

Goutas

Outskouni

Papathanasiou

et al. 2021

Cells

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We recently reported that the inability of osteoarthritic (OA) chondrocytes to repair oxidative stress (OS) induced DNA damage is linked to Cav-1 overexpression/improper localization. We speculated that the senescent status of OA cells was responsible for this Cav-1 dysregulation. Here, to further investigate this hypothesis, we used Wharton Jelly derived mesenchymal stem cells (WJ-MSCs) and investigated Cav-1 function as cells reached replicative senescence or upon stress induced senescence (SIPS). We showed that Cav-1 is upregulated, phosphorylated and translocated to the nucleus in young WJ-MSCs upon acute exogenous OS, and that it returns back to basal/nonphosphorylated levels and exports the nucleus in the recovery phase. However, as cells reach senescence, this regulation is lost. OS did not induce any Cav-1-mediated response, which is concomitant with the inability of older cells to restore DNA damage. Furthermore, downregulation of Cav-1 resulted in persistent OS-induced DNA damage and subsequent onset of senescence. We also report that the establishment of senescence is mediated by autophagy stimulation, since downregulation of autophagy key molecule Atg5, simultaneously with Cav-1 downregulation, was found to inhibit SIPS. Basically, we propose that Cav-1 involvement in DNA damage response can lead to senescence, either because the damage is extensive or because Cav-1 is absent/unable to perform its homeostatic role.

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Coordinate regulation of the senescent state by selective autophagy

Cited by 40 publications

References 76 publications

TNIP1 inhibits Mitophagy via interaction with FIP200 and TAX1BP1

TNIP1 inhibits Mitophagy via interaction with FIP200 and TAX1BP1

Biochemical and Cellular Characterization of New Radio-Resistant Cell Lines Reveals a Role of Natural Flavonoids to Bypass Senescence

Dysregulation of Caveolin-1 Phosphorylation and Nuclear Translocation Is Associated with Senescence Onset

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