Chaperone-Independent Peripheral Quality Control of CFTR by RFFL E3 Ligase

Okiyoneda, Tsukasa; Veit, Guido; Sakai, Ryohei; Aki, Misaki; Fujihara, Takeshi; Higashi, Momoko; Susuki-Miyata, Seiko; Miyata, Masanori; Fukuda, Norihito; Yoshida, Akihiko; Xu, Haijin; Apaja, Pirjo M.; Lukacs, Gergely L.

doi:10.1016/j.devcel.2018.02.001

Cited by 63 publications

(139 citation statements)

References 85 publications

(158 reference statements)

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“…and El-Deiry, 2004). Interestingly, CARP2-positive vesicles are also reported to be 69 positive for Rab5, Rab7, Rab9, Rab11 and Lamp1 markers of diverse endocytic vesicles 70 (Coumailleau et al, 2004;Liao et al, 2008;Okiyoneda et al, 2018). In this study, we 71 report that CARP2-positive vesicles associate with damaged mitochondria.…”

Section: Introductionsupporting

confidence: 50%

Endosomes facilitate mitochondrial clearance by enhancing Parkin recruitment to mitochondria

Ravindran

Velikkakath

Narendradev

et al. 2020

Preprint

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13Mitochondrial quality control and homeostasis is ensured by removal of the damaged 14 mitochondria involving lysosomal and proteasomal degradation mechanisms. Though 15 much remains to be elucidated, recent findings suggest important roles for endosomal 16 machinery in the elimination of damaged mitochondria. In this study, we report a novel 17 function for a FYVE-like domain containing endosomal ubiquitin ligase, CARP2 in 18 mitophagy. Our results show that endosomal CARP2 associates with damaged 19 mitochondria, and this association precedes that of Parkin, whose recruitment is known 20 to be essential for mitochondrial clearance. Association of Parkin to damaged 21 mitochondria was substantially reduced in CARP2 KO cells upon CCCP treatment. We 22 also demonstrate that Mitofusin-2 degradation, which is a prerequisite for Parkin 23 recruitment during damage, was inhibited in CARP2-deficient cells. Hence, we conclude 24 that endosomal-associated CARP2 facilitates mitophagy by regulating Parkin recruitment 25 and activation by targeting Mitofusin-2. Our study proposes a model on how 26 heterogenous endocytic machinery can interact with damaged mitochondria and unravel 27 a new mechanism for mitochondrial clearance. 28 29 30 31 32 33 Stringent quality control mechanisms ensure organelle and cellular homeostasis. 34 Signaling pathways that regulate mitochondrial quality and function are believed to play 35 critical roles in diverse physiological processes including cell survival and their 36 dysregulation results in the development of numerous pathological conditions like 37 neurological disorders, cancer and myopathies (Arun, Liu and Donmez, 2015; Ahuja, 38 2018; Porporato et al., 2018). Autophagy is a conserved intracellular catabolic process in 39 which cytoplasmic contents, including damaged mitochondria, are sequestered in double-40 membrane autophagosomes and delivered to the lysosomal compartment for 41 degradation (Dikic, 2017). Selective elimination of dysfunctional and damaged 42 mitochondria involving autophagic machinery and lysosomes is known as mitophagy 43 (Montava-Garriga and Ganley, 2020). 44 Though cells can employ various other cellular tools like ESCRT machinery (Hammerling 45 et al., 2017), MDVs (Mitochondrial Derived Vesicles) (Sugiura et al., 2014; McLelland et 46 al., 2016) etc., to remove mitochondrial contents, mitophagy mediated by PINK1/Parkin 47 is relatively well studied (Narendra et al., 2008(Narendra et al., , 2010 Durcan and Fon, 2015). In 48 depolarized mitochondria, PINK1 accumulated on the outer mitochondrial membrane 49 phosphorylates Parkin which in turn pleiotropically ubiquitinates Mfn2 resulting in its 50 degradation. Mfn2 degradation mediated by Parkin is believed to be a critical step in 51 Parkin stabilization and mitophagy, as Mfn2 regulates physical attachment of 52 mitochondria to ER. Many details of the sequence of events involved in Parkin 53 recruitment, stabilization and identity of proteins are not available. 54 Recent reports, however, suggested a role...

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Section: Introductionsupporting

confidence: 50%

Endosomes facilitate mitochondrial clearance by enhancing Parkin recruitment to mitochondria

Ravindran

Velikkakath

Narendradev

et al. 2020

Preprint

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“…For example, in a recent report RFFL was shown to mediate retrieval from the plasma membrane and subsequent lysosomal degradation of a non-native CFTR mutant via interaction and K63-polyubiquitylation in a post-Golgi compartment. (Okiyoneda et al, 2018). In this context, cooperation with UBC13 appears plausible.…”

Section: Selectivity Of E2-e3 Pairingmentioning

confidence: 95%

“…Accordingly, the protein has been reported to modify a diverse set of substrates, many of them localising to the plasma membrane or endocytic vesicles Liao et al, 2008;Okiyoneda et al, 2018). RFFL was often observed to act redundantly with a closely related protein, RNF34 (also called CARP1 or Momo) Liao et al, 2009).…”

Section: Selectivity Of E2-e3 Pairingmentioning

confidence: 99%

“…RFFL was often observed to act redundantly with a closely related protein, RNF34 (also called CARP1 or Momo) Liao et al, 2009). Whereas most instances of RFFL-and/or RNF34-mediated ubiquitylation appear to involve proteasomal degradation Liao et al, 2009;Liao et al, 2008;Wei et al, 2012;Yang et al, 2007;Zhang et al, 2014), there are cases where a contribution of lysosomal proteolysis has been demonstrated (Jin et al, 2014;Okiyoneda et al, 2018). For example, in a recent report RFFL was shown to mediate retrieval from the plasma membrane and subsequent lysosomal degradation of a non-native CFTR mutant via interaction and K63-polyubiquitylation in a post-Golgi compartment.…”

Section: Selectivity Of E2-e3 Pairingmentioning

confidence: 99%

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The ubiquitin-conjugating enzyme Ubc13-Mms2 cooperates with a family of FYVE-type-RING ubiquitin protein ligases in K63-polyubiquitylation at internal membranes

Renz¹,

Troester²,

Albert

et al. 2019

Preprint

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KEYWORDSFYVE domain / K63-polyubiquitylation / membrane protein sorting / RING finger / ubiquitin protein ligase / ubiquitin-conjugating enzyme ABSTRACTThe heterodimeric ubiquitin-conjugating enzyme (E2), Ubc13-Mms2, catalyses K63-specific polyubiquitylation in genome maintenance and inflammatory signalling. In budding yeast, the only ubiquitin protein ligase (E3) known to cooperate with Ubc13-Mms2 so far is a nuclear RING finger protein, Rad5, involved in the replication of damaged DNA. We have now identified a family of membrane-associated FYVE-(type)-RING finger proteins as cognate E3s for Ubc13-Mms2 in several species. We show that budding yeast Pib1, a FYVE-RING finger E3 associated with internal membranes, exhibits exquisite selectivity for Ubc13-Mms2 and cooperates with the E2 in the multivesicular body pathway. Phenotypic analysis indicates that the contribution of Ubc13-Mms2 to membrane trafficking goes beyond its cooperation with Pib1, suggesting an involvement with additional E3s in the endocytic compartment. These results widely implicate Ubc13-Mms2 in the regulation of membrane protein sorting.

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“…Given the long cellular and PM half-life of CFTR (Okiyoneda et al, 2018;Varga et al, 2008), slow internalization rate with high fidelity of apical recycling is essential to maintain Cltransport capacity by minimizing the channel premature degradation and basolateral missorting.…”

Section: Introductionmentioning

confidence: 99%

Transcytosis maintains CFTR apical polarity in the face of constitutive and mutation-induced basolateral missorting

Bidaud-Meynard

Bossard

Schnúr

et al. 2018

Preprint

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2 SUMMARYApical polarity of cystic fibrosis transmembrane conductance regulator (CFTR) is essential for solute and water transport in secretory epithelia and can be impaired in human diseases. Maintenance of apical polarity in the face of CFTR non-polarized delivery and compromised apical retention of mutant CFTRs lacking PDZ-domain protein (NHERF1) interaction, remains enigmatic. Here we show that basolateral CFTR delivery originates from biosynthetic (~35%) and endocytic (~65%) recycling missorting. Basolateral channels are retrieved via basolateral-to-apical transcytosis, enhancing CFTR apical expression by two-fold and suppressing its degradation. CFTR transcytosis is microtubuledependent but independent of Myo5B-, Rab11-and NHERF1 binding to its C-terminal DTRL motif in airway epithelia. Increased basolateral delivery due to compromised apical recycling and accelerated internalization upon impaired NHERF1-CFTR association is largely counterbalanced by CFTR efficient basolateral internalization and apical transcytosis. Thus, transcytosis represents a previously unrecognized but indispensable mechanism for maintaining CFTR apical polarity by attenuating its constitutive and mutation-induced basolateral missorting. 4

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Chaperone-Independent Peripheral Quality Control of CFTR by RFFL E3 Ligase

Cited by 63 publications

References 85 publications

Endosomes facilitate mitochondrial clearance by enhancing Parkin recruitment to mitochondria

Endosomes facilitate mitochondrial clearance by enhancing Parkin recruitment to mitochondria

The ubiquitin-conjugating enzyme Ubc13-Mms2 cooperates with a family of FYVE-type-RING ubiquitin protein ligases in K63-polyubiquitylation at internal membranes

Transcytosis maintains CFTR apical polarity in the face of constitutive and mutation-induced basolateral missorting

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