Digest it all: the lysosomal turnover of cytoplasmic aggregates

Mauthe, Mario; Kampinga, Harm H.; Hipp, Mark S.; Reggiori, Fulvio

doi:10.1016/j.tibs.2022.09.012

Cited by 8 publications

(2 citation statements)

References 99 publications

(219 reference statements)

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“…It has been demonstrated that polyubiquitination of proteins target them for degradation by various routes including the lysosomal pathway. 34 Consistently, we found that PD-L1 induced polyubiquitination and down-regulation of γ c in Jurkat-PD1 cells, which was most dramatic at 2 days after PD-L1 stimulation (Fig. 2d).…”

Section: Introductionsupporting

confidence: 84%

PD-1 signaling negatively regulates the common cytokine receptor γ chain via MARCH5-mediated ubiquitination and degradation to suppress anti-tumor immunity

Liu,

Zeng,

et al. 2023

Cell Res

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Combination therapy with PD-1 blockade and IL-2 substantially improves anti-tumor efficacy comparing to monotherapy. The underlying mechanisms responsible for the synergistic effects of the combination therapy remain enigmatic. Here we show that PD-1 ligation results in BATF-dependent transcriptional induction of the membrane-associated E3 ubiquitin ligase MARCH5, which mediates K27-linked polyubiquitination and lysosomal degradation of the common cytokine receptor γ chain (γc). PD-1 ligation also activates SHP2, which dephosphorylates γcY357, leading to impairment of γc family cytokine-triggered signaling. Conversely, PD-1 blockade restores γc level and activity, thereby sensitizing CD8+ T cells to IL-2. We also identified Pitavastatin Calcium as an inhibitor of MARCH5, which combined with PD-1 blockade and IL-2 significantly improves the efficacy of anti-tumor immunotherapy in mice. Our findings uncover the mechanisms by which PD-1 signaling antagonizes γc family cytokine-triggered immune activation and demonstrate that the underlying mechanisms can be exploited for increased efficacy of combination immunotherapy of cancer.

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Section: Introductionsupporting

confidence: 84%

PD-1 signaling negatively regulates the common cytokine receptor γ chain via MARCH5-mediated ubiquitination and degradation to suppress anti-tumor immunity

Liu,

Zeng,

et al. 2023

Cell Res

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“…Very recently, the induced translocation of a ubiquitin E3 ligase, STIP1 Homology and U-Box Containing Protein 1 (Stub1), was shown to promote the turnover of oxidized peroxisomes through ubiquitination-dependent pexophagy ( Figure 3 C) [ 288 ]. Organellophagy is also involved in the turnover of other organelles and proteins, including lysosomes (lysophagy) [ 289 , 290 , 291 ], nuclei (nucleophagy) [ 270 , 292 ], ribosomes (ribophagy) [ 293 , 294 , 295 ], protein aggregates (aggrephagy) [ 198 , 296 , 297 , 298 , 299 ], LDs (lipophagy) [ 300 , 301 , 302 , 303 ], and ferritin (ferritinophagy) [ 304 , 305 , 306 , 307 ], through specific cognate cargo receptors ( Figure 3 C).…”

Section: Autophagymentioning

confidence: 99%

Crosstalk between Autophagy and RLR Signaling

2023

Cells

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Autophagy plays a homeostatic role in regulating cellular metabolism by degrading unwanted intracellular materials and acts as a host defense mechanism by eliminating infecting pathogens, such as viruses. Upon viral infection, host cells often activate retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) signaling to induce the transcription of type I interferons, thus establishing the first line of the innate antiviral response. In recent years, numerous studies have shown that virus-mediated autophagy activation may benefit viral replication through different actions on host cellular processes, including the modulation of RLR-mediated innate immunity. Here, an overview of the functional molecules and regulatory mechanism of the RLR antiviral immune response as well as autophagy is presented. Moreover, a summary of the current knowledge on the biological role of autophagy in regulating RLR antiviral signaling is provided. The molecular mechanisms underlying the crosstalk between autophagy and RLR innate immunity are also discussed.

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