Zhang &amp; Manning reply

Zhang, Yinan; Manning, Brendan D.

doi:10.1038/nature16473

Cited by 12 publications

(15 citation statements)

References 8 publications

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“…The different observations of the involvement do not fit into one coherent model yet. Acute TORC1 inhibition by rapamycin promotes proteolysis via ERK5 [116,117] in order to gain free amino acids for TOR1 re-activation, while prolonged TORC1 activation also seems to trigger an increased protein turnover via the transcription factor erythroid-derived 2-related factor 1 (NRF1) [118,119,120] in order to balance the increased rate of protein synthesis.…”

Section: Downstream Factors Of Mtor Signalingmentioning

confidence: 99%

mTOR: A Cellular Regulator Interface in Health and Disease

Boutouja

Stiehm

Platta

2019

Cells

115

110

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The mechanistic target of Rapamycin (mTOR) is a ubiquitously-conserved serine/threonine kinase, which has a central function in integrating growth signals and orchestrating their physiologic effects on cellular level. mTOR is the core component of differently composed signaling complexes that differ in protein composition and molecular targets. Newly identified classes of mTOR inhibitors are being developed to block autoimmune diseases and transplant rejections but also to treat obesity, diabetes, and different types of cancer. Therefore, the selective and context-dependent inhibition of mTOR activity itself might come into the focus as molecular target to prevent severe diseases and possibly to extend life span. This review provides a general introduction to the molecular composition and physiologic function of mTOR complexes as part of the Special Issue “2018 Select Papers by Cells’ Editorial Board Members”.

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Section: Downstream Factors Of Mtor Signalingmentioning

confidence: 99%

mTOR: A Cellular Regulator Interface in Health and Disease

Boutouja

Stiehm

Platta

2019

Cells

115

110

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“…In addition, mTOR signalling negatively regulates proteasomal activity in MEFs and in HEK293 cells [40]. Regarding proteasomal activity, the opposite is also observed, namely that mTOR signalling positively governs proteasomal activity as was shown in MEFs and in HEK293 cells [162], leading to an unresolved situation [163,164].…”

Section: Which Role Does the Primary Cilium Play In The Crosstalk mentioning

confidence: 99%

The Role of Primary Cilia in the Crosstalk between the Ubiquitin–Proteasome System and Autophagy

Wiegering

Rüther

Gerhardt

2019

Cells

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Protein degradation is a pivotal process for eukaryotic development and homeostasis. The majority of proteins are degraded by the ubiquitin–proteasome system and by autophagy. Recent studies describe a crosstalk between these two main eukaryotic degradation systems which allows for establishing a kind of safety mechanism. If one of these degradation systems is hampered, the other compensates for this defect. The mechanism behind this crosstalk is poorly understood. Novel studies suggest that primary cilia, little cellular protrusions, are involved in the regulation of the crosstalk between the two degradation systems. In this review article, we summarise the current knowledge about the association between cilia, the ubiquitin–proteasome system and autophagy.

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“…Moreover, it was reported that MTORC1 signaling does not only negatively control autophagic activity but also negatively regulates proteasomal activity [ 91 ]. However, another report described the opposite, namely that MTORC1 signaling positively governs proteasomal activity [ 92 ] leading to a controversial debate[ 93 , 94 ]. Our current study revealed that RPGRIP1L deficiency results in elevated MTORC1 signaling ( Figure 2A and C , Figure 3G ) and our previous study showed that overall proteasomal activity is unaltered in rpgrip1l −/− MEFs [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

The ciliary protein RPGRIP1L governs autophagy independently of its proteasome-regulating function at the ciliary base in mouse embryonic fibroblasts

et al. 2018

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Previously, macroautophagy/autophagy was demonstrated to be regulated inter alia by the primary cilium. Mutations in RPGRIP1L cause ciliary dysfunctions resulting in severe human diseases summarized as ciliopathies. Recently, we showed that RPGRIP1L deficiency leads to a decreased proteasomal activity at the ciliary base in mice. Importantly, the drug-induced restoration of proteasomal activity does not rescue ciliary length alterations in the absence of RPGRIP1L indicating that RPGRIP1L affects ciliary function also via other mechanisms. Based on this knowledge, we analyzed autophagy in Rpgrip1l-negative mouse embryos. In these embryos, autophagic activity was decreased due to an increased activation of the MTOR complex 1 (MTORC1). Application of the MTORC1 inhibitor rapamycin rescued dysregulated MTORC1, autophagic activity and cilia length but not proteasomal activity in Rpgrip1l-deficient mouse embryonic fibroblasts demonstrating that RPGRIP1L seems to regulate autophagic and proteasomal activity independently from each other.

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Zhang & Manning reply

Cited by 12 publications

References 8 publications

mTOR: A Cellular Regulator Interface in Health and Disease

mTOR: A Cellular Regulator Interface in Health and Disease

The Role of Primary Cilia in the Crosstalk between the Ubiquitin–Proteasome System and Autophagy

The ciliary protein RPGRIP1L governs autophagy independently of its proteasome-regulating function at the ciliary base in mouse embryonic fibroblasts

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