Structural basis for autophagy inhibition by the human Rubicon–Rab7 complex

Bhargava, Hersh K.; Tabata, Keisuke; Byck, Jordan M; Hamasaki, Maho; Farrell, Daniel P.; Anishchenko, Ivan; DiMaio, Frank; Im, Young Jun; Yoshimori, Tamotsu; Hurley, James H.

doi:10.1073/pnas.2008030117

Cited by 21 publications

(26 citation statements)

References 38 publications

(58 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Additionally, RAB7 overexpression induced chemosensitization of cisplatin-resistant cells, while depletion of RAB7 by siRNA induced resistance to cisplatin in chemosensitive cells ( 108 ). Furthermore, RUBICON (Run domain Beclin-1 interacting and cysteine-rich containing), a negative regulator of autophagy, inhibits autophagosome-lysosome fusion and interacts with RAB7-GTP via a RUBICON homology (RH) domain ( 109 ).…”

Section: Impact Of Inhibiting Autophagosome-lysosome Fusion On the Rementioning

confidence: 99%

Targeting Cytoprotective Autophagy to Enhance Anticancer Therapies

et al. 2021

View full text Add to dashboard Cite

Autophagy is a highly regulated multi-step process that occurs at the basal level in almost all cells. Although the deregulation of the autophagy process has been described in several pathologies, the role of autophagy in cancer as a cytoprotective mechanism is currently well established and supported by experimental and clinical evidence. Our understanding of the molecular mechanism of the autophagy process has largely contributed to defining how we can harness this process to improve the benefit of cancer therapies. While the role of autophagy in tumor resistance to chemotherapy is extensively documented, emerging data point toward autophagy as a mechanism of cancer resistance to radiotherapy, targeted therapy, and immunotherapy. Therefore, manipulating autophagy has emerged as a promising strategy to overcome tumor resistance to various anti-cancer therapies, and autophagy modulators are currently evaluated in combination therapies in several clinical trials. In this review, we will summarize our current knowledge of the impact of genetically and pharmacologically modulating autophagy genes and proteins, involved in the different steps of the autophagy process, on the therapeutic benefit of various cancer therapies. We will also briefly discuss the challenges and limitations to developing potent and selective autophagy inhibitors that could be used in ongoing clinical trials.

show abstract

Section: Impact Of Inhibiting Autophagosome-lysosome Fusion On the Rementioning

confidence: 99%

Targeting Cytoprotective Autophagy to Enhance Anticancer Therapies

et al. 2021

View full text Add to dashboard Cite

show abstract

“…In the absence of high-resolution homologous structures, the method is able to determine structures to an atomic level of detail. In addition to cryoEM data, we have recently shown that a similar approach can be applied to solve low-resolution crystal structure data where traditional molecular replacement techniques were unsuccessful (Bhargava et al, 2020). We expect that the modeling power of trRosetta and related techniques will continue to improve in the future as the number of known sequences increases, coupled with improvements in deeplearning methodologies.…”

Section: Discussionmentioning

confidence: 99%

Deep learning enables the atomic structure determination of the Fanconi Anemia core complex from cryoEM

Farrell

Anishchenko

Shakeel

et al. 2020

Int Union Crystallogr J

Self Cite

View full text Add to dashboard Cite

Cryo-electron microscopy of protein complexes often leads to moderate resolution maps (4–8 Å), with visible secondary-structure elements but poorly resolved loops, making model building challenging. In the absence of high-resolution structures of homologues, only coarse-grained structural features are typically inferred from these maps, and it is often impossible to assign specific regions of density to individual protein subunits. This paper describes a new method for overcoming these difficulties that integrates predicted residue distance distributions from a deep-learned convolutional neural network, computational protein folding using Rosetta, and automated EM-map-guided complex assembly. We apply this method to a 4.6 Å resolution cryoEM map of Fanconi Anemia core complex (FAcc), an E3 ubiquitin ligase required for DNA interstrand crosslink repair, which was previously challenging to interpret as it comprises 6557 residues, only 1897 of which are covered by homology models. In the published model built from this map, only 387 residues could be assigned to the specific subunits with confidence. By building and placing into density 42 deep-learning-guided models containing 4795 residues not included in the previously published structure, we are able to determine an almost-complete atomic model of FAcc, in which 5182 of the 6557 residues were placed. The resulting model is consistent with previously published biochemical data, and facilitates interpretation of disease-related mutational data. We anticipate that our approach will be broadly useful for cryoEM structure determination of large complexes containing many subunits for which there are no homologues of known structure.

show abstract

“…Interestingly, LAP and the formation of LC3-associated efferosomes is dependent on the Beclin1-interacting protein Rubicon ( 39 ). Rubicon is a negative regulator of canonical autophagy and downregulation of this protein results in an increase in the number of autophagosomes ( 39 , 40 ). Indeed, deletion of Rubicon in a mouse model of autoimmune disease significantly increases susceptibility to the development of systemic lupus erythematosus-like features in these animals, potentially due to altered processing of apoptotic cells ( 41 ).…”

Section: Efferosome Trafficking and Antigen Presentationmentioning

confidence: 99%

Cellular Responses to the Efferocytosis of Apoptotic Cells

Yin

Heit

2021

Front. Immunol.

View full text Add to dashboard Cite

The rapid and efficient phagocytic clearance of apoptotic cells, termed efferocytosis, is a critical mechanism in the maintenance of tissue homeostasis. Removal of apoptotic cells through efferocytosis prevents secondary necrosis and the resultant inflammation caused by the release of intracellular contents. The importance of efferocytosis in homeostasis is underscored by the large number of inflammatory and autoimmune disorders, including atherosclerosis and systemic lupus erythematosus, that are characterized by defective apoptotic cell clearance. Although mechanistically similar to the phagocytic clearance of pathogens, efferocytosis differs from phagocytosis in that it is immunologically silent and induces a tissue repair response. Efferocytes face unique challenges resulting from the internalization of apoptotic cells, including degradation of the apoptotic cell, dealing with the extra metabolic load imposed by the processing of apoptotic cell contents, and the coordination of an anti-inflammatory, pro-tissue repair response. This review will discuss recent advances in our understanding of the cellular response to apoptotic cell uptake, including trafficking of apoptotic cell cargo and antigen presentation, signaling and transcriptional events initiated by efferocytosis, the coordination of an anti-inflammatory response and tissue repair, unique cellular metabolic responses and the role of efferocytosis in host defense. A better understanding of how efferocytic cells respond to apoptotic cell uptake will be critical in unraveling the complex connections between apoptotic cell removal and inflammation resolution and maintenance of tissue homeostasis.

show abstract

Structural basis for autophagy inhibition by the human Rubicon–Rab7 complex

Cited by 21 publications

References 38 publications

Targeting Cytoprotective Autophagy to Enhance Anticancer Therapies

Targeting Cytoprotective Autophagy to Enhance Anticancer Therapies

Deep learning enables the atomic structure determination of the Fanconi Anemia core complex from cryoEM

Cellular Responses to the Efferocytosis of Apoptotic Cells

Contact Info

Product

Resources

About