HIP1R targets PD-L1 to lysosomal degradation to alter T cell–mediated cytotoxicity

Wang, Huanbin; Yao, Han; Li, Chushu; Shi, Hubing; Jiang, Lan; Li, Zhaoli; Zhang, Y; Liang, Luming; Fang, Jing‐Yuan; Xu, Jie

doi:10.1038/s41589-018-0161-x

Cited by 202 publications

(179 citation statements)

References 53 publications

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“…It was reported that the chaperone-mediated autophagy (CMA) motifs have been used to target cytosolic proteins including huntingtin27, DAPK1, DLG4 and αsynuclein, which are not affected by 3-MA [29,30]. Also, Jie Xu et al reported that Huntingtin-interacting protein 1-related protein (HIP1R) was involved in mediating lysosomal degradation of PD-L1, but the inhibitors for autophagy (3-MA) displayed no effect on HIP1R [31]. Thus, it might be important to further investigate which stage of lysosome-mediated degradative pathways, i.e., endocytic, autophagic, or phagocytic pathways, is influenced by C19orf66, and which lysosome-related molecules interact with C19orf66 to mediate NS3 degradation.…”

Section: Discussionmentioning

confidence: 99%

C19orf66 interrupts Zika virus replication by inducing lysosomal degradation of viral NS3

Yang

Yao

et al. 2020

PLoS Negl Trop Dis

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The rapidly emerging human health crisis associated with the Zika virus (ZIKV) epidemic and its link to severe complications highlights the growing need to identify the mechanisms by which ZIKV accesses hosts. Interferon response protects host cells against viral infection, while the cellular factors that mediate this defense are the products of interferon-stimulated genes (ISGs). Although hundreds of ISGs have been identified, only a few have been characterized for their antiviral potential, target specificity and mechanisms of action. In this work, we focused our investigation on the possible antiviral effect of a novel ISG, C19orf66 in response to ZIKV infection and the associated mechanisms. We found that ZIKV infection could induce C19orf66 expression in ZIKV-permissive cells, and such an overexpression of C19orf66 remarkably suppressed ZIKV replication. Conversely, the depletion of C19orf66 led to a significant increase in viral replication. Furthermore, C19orf66 was found to interact and co-localize with ZIKV nonstructural protein 3 (NS3), thus inducing NS3 degradation via a lysosome-dependent pathway. Taken together, this study identified C19orf66 as a novel ISG that exerts antiviral effects against ZIKV by specifically degrading a viral nonstructural protein. These findings uncovered an intriguing mechanism of C19orf66 that targeting NS3 protein of ZIKV, providing clues for understanding the actions of innate immunity, and affording the possible availability of new drug targets that can be used for therapeutic intervention. "Guangdong Te Zhi program" youth science and technology talent of project (2015TQ01R281); Guangdong MEDP Fund Author summary ZIKV represents a serious threat to global health with particular relevance to microcephaly and other congenital abnormalities in newborns, and Guillain-Barré syndrome, meningoencephalitis, multi-organ failure in adults. Despite the global health threat of Zika virus infection, there is currently no vaccine or effective antiviral therapy available for the disease. As widely recognized, interferon signaling is key to establishing a strong antiviral state in host cells, mainly mediated through the anti-viral effects of numerous interferon-stimulated genes (ISGs). This work described our novel finding of the antiviral effect of a novel ISG, C19orf66, and its underlying mechanisms. We identified C19orf66 as a novel ISG that exerts antiviral effects against ZIKV by specifically interacting and colocalizing with the ZIKV nonstructural (NS) protein NS3, which inducing NS3 degradation via a lysosome-dependent pathway. Thus, this work broadens the understanding of the pivotal roles of C19orf66 in the interaction between the host and ZIKV, which might further provide a rational basis for developing novel anti-ZIKV strategies. PLOS NEGLECTED TROPICAL DISEASESC19orf66 suppresses ZIKV replication by target viral NS3 PLOS Neglected Tropical Diseases | https://doi.org/10.

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Section: Discussionmentioning

confidence: 99%

C19orf66 interrupts Zika virus replication by inducing lysosomal degradation of viral NS3

Yang

Yao

et al. 2020

PLoS Negl Trop Dis

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“…[ 100 ] Moreover, a similar peptide, KLKKQ, which is derived from the Huntingtin‐interacting protein 1–related (HIP1R) protein, was shown to interact with programmed death ligand 1 (PDL1) and direct the lysosomal proteolysis of PDL1, and the green fluorescent protein fused with this peptide can also be degraded through a lysosome‐dependent pathway. [ 101 ]…”

Section: Reagents Involved In Selective Protein Degradationmentioning

confidence: 99%

Significance of Selective Protein Degradation in the Development of Novel Targeted Drugs and Its Implications in Cancer Therapy

Yang

Wang

Feng

et al. 2020

Advanced Therapeutics

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The evolution of traditional chemotherapeutic drugs to targeted drugs has led to major changes in cancer treatment. However, it remains difficult to develop effective targeted drugs that can act against “undruggable” proteins, including some well‐known oncoproteins such as KRas. Moreover, mutations of target genes limit the use of targeted drugs. Although some strategies such as RNA interference and DNA editing have been adopted to solve these problems, their clinical use remains challenging. Therefore, new strategies are urgently needed to meet the dilemmas encountered in the use of targeted drugs. As protein degradation is a rapid and well‐regulated biological process in cells, targeting protein degradation by inducing cellular protein degradation machinery, regardless of the status of the target, is an attractive idea for developing novel targeted drugs. This review summarizes recent advances in targeted protein degradation, with a focus on the current reagents and strategies used for inducing selective degradation of target proteins to provide clues for the development of novel anticancer drugs and cancer therapies.

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“…In addition to the ER related quality control regulation of PD‐L1 trafficking, recent studies also show that the protein HIP1R in the clathrin‐mediated endocytosis pathway targets PD‐L1 to lysosomal degradation, to alter T‐cell–mediated cytotoxicity . HIP1R interacts with PD‐L1 and delivers PD‐L1 to the lysosome through a lysosomal targeting signal, whereas depletion of HIP1R in tumour cells causes the accumulation of PD‐L1 and suppression of T‐cell cytotoxicity, suggesting that lysosomal degradation of the membrane PD‐L1 is a critical pathway in the negative checkpoint functionality . When a rationally designed peptide (PD‐LYSO) incorporating the lysosome‐sorting signal and the PD‐L1‐binding sequence of HIP1R was developed and tested, PD‐L1 is successfully depleted, used to deplete PD‐L1 in tumour cells, demonstrating a chimeric peptide for targeted degradation of PD‐L1 in lysosomes …”

Section: Pd‐l1 Phosphorylation Palmitoylation Intracellular and Extmentioning

confidence: 99%

Undo the brake of tumour immune tolerance with antibodies, peptide mimetics and small molecule compounds targeting PD‐1/PD‐L1 checkpoint at different locations for acceleration of cytotoxic immunity to cancer cells

Wang

et al. 2019

Clin Exp Pharma Physio

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Summary Recent clinical success of immunotherapy that inhibits the negative immune regulatory pathway programmed cell death protein‐1/PD‐1 ligand 1 (PD‐1/PD‐L1) has initiated a new era in the treatment of metastatic cancer. However, greater challenges remain to treat all cancers. The molecular architecture in the immune synapse constituting positive engagements for immune activation and negative checkpoints against immune hyperactivity is regulated dynamically by interaction between proteostasis and tumour microenvironment. This article reviews recent progresses in our understandings of the cellular and molecular mechanisms of the negative checkpoint PD‐1/PD‐L1 behaviours in immune tolerance of tumourigenesis and metastasis. We provide an overview on PD‐L1 gene expression regulation, protein turnover, intra‐ and extracellular trafficking, exosome‐mediated inter‐cellular transport, molecular interface peptide mimetics, inhibitory chemical compounds such as metformin, and antibody dynamics. We summarise PD‐L1 post‐translational modifications including glycosylation, palmitoylation, phosphorylation and ubiquitination, reflecting future research directions and opportunities in identifying tumour‐specific signalling targets, their regulatory molecules and pathways for intervention into various types of cancers.

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HIP1R targets PD-L1 to lysosomal degradation to alter T cell–mediated cytotoxicity

Cited by 202 publications

References 53 publications

C19orf66 interrupts Zika virus replication by inducing lysosomal degradation of viral NS3

C19orf66 interrupts Zika virus replication by inducing lysosomal degradation of viral NS3

Significance of Selective Protein Degradation in the Development of Novel Targeted Drugs and Its Implications in Cancer Therapy

Undo the brake of tumour immune tolerance with antibodies, peptide mimetics and small molecule compounds targeting PD‐1/PD‐L1 checkpoint at different locations for acceleration of cytotoxic immunity to cancer cells

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