Viral strategies for triggering and manipulating mitophagyZhang, Linliang; Qin, Yali; Chen, Mingzhou
doi: 10.1080/15548627.2018.1466014pmid: 29895192
Viral infection causes many physiological alterations in the host cell, and many of these alterations can affect the host mitochondrial network, including mitophagy induction. A substantial amount of literature has been generated that advances our understanding of the relationship between mitophagy and several viruses. Some viruses trigger mitophagy directly, and indirectly and control the mitophagic process via different strategies. This enables viruses to promote persistent infection and attenuate the innate immune responses. In this review, we discuss the events of virus-regulated mitophagy and the functional relevance of mitophagy in the pathogenesis of viral infection and disease.Abbreviation: ATG: autophagy related; BCL2L13: BCL2 like 13; BNIP3L/NIX: BCL2 interacting protein 3 like; CL: cardiolipin; CSFV: classical swine fever virus; CVB: coxsackievirus B; DENV: dengue virus; DNM1L: dynamin 1 like; FIS1: fission, mitochondrial 1; FUNDC1: FUN14 domain containing 1; HPIV3: human parainfluenza virus 3; HSV-1: herpes simplex virus type 1; IMM: inner mitochondrial membrane; IAV: influenza A virus; IFN: interferon; IKBKE/IKKε: inhibitor of nuclear factor kappa B kinase subunit epsilon; LUBAC: linear ubiquitin assembly complex; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MeV: measles virus; MAVS: mitochondrial antiviral signaling protein; MFF: mitochondria fission factor; NLRP3: NLR family pyrin domain containing 3; NDV: Newcastle disease virus; NR4A1: nuclear receptor subfamily 4 group A member 1; OMM: outer mitochondrial membrane; OPA1: OPA1, mitochondrial dynamin like GTPase; PRKN: parkin RBR E3 ubiquitin protein ligase; PINK1: PTEN induced putative kinase 1; PHB2: prohibitin 2; PRRSV: porcine reproductive and respiratory syndrome virus; PRRs: pattern-recognition receptors; RLRs: RIG-I-like receptors; ROS: reactive oxygen species; RIPK2: receptor interacting serine/threonine kinase 2; SESN2: sestrin 2; SNAP29: synaptosome associated protein 29; STX17: syntaxin 17; TGEV: transmissible gastroenteritis virus; TUFM: Tu translation elongation factor, mitochondrial; TRAF2: TNF receptor associated factor 2; TRIM6: tripartite motif containing 6; Ub: ubiquitin; ULK1: unc-51 like autophagy activating kinase 1; VZV: varicella-zoster virus
The phagophore in four dimensions—a study in woodSewell, John C.; Klionsky, Daniel J.
doi: 10.1080/15548627.2018.1493315pmid: 30009664
One of the key features of macroautophagy/autophagy is the dynamic nature of the membrane rearrangements that take place during expansion of the phagophore, the sequestering compartment that matures into an autophagosome. There are various ways to depict this process, but in most cases the method ultimately relies on a two-dimensional medium. Most people working in the field of autophagy realize that the typical ‘C’-shaped drawing of a phagophore is meant to represent a cup- or bowl-like structure that exists in the cell in 3 dimensions. However, explaining this concept to a lay person often leads to confusion and misinterpretation. Accordingly, we decided to generate a four-dimensional version of the expanding phagophore as a wood sculpture, that depicts this transient compartment in 3 dimensions over time.Abbreviations: ER: endoplasmic reticulum
Interaction between autophagic vesicles and the Coxiella-containing vacuole requires CLTC (clathrin heavy chain)Latomanski, Eleanor A.; Newton, Hayley J.
doi: 10.1080/15548627.2018.1483806pmid: 29973118
Coxiella burnetii is an intracellular bacterial pathogen which causes Q fever, a human infection with the ability to cause chronic disease with potentially life-threatening outcomes. In humans, Coxiella infects alveolar macrophages where it replicates to high numbers in a unique, pathogen-directed lysosome-derived vacuole. This compartment, termed the Coxiella-containing vacuole (CCV), has a low internal pH and contains markers both of lysosomes and autophagosomes. The CCV membrane is also enriched with CLTC (clathrin heavy chain) and this contributes to the success of the CCV. Here, we describe a role for CLTC, a scaffolding protein of clathrin-coated vesicles, in facilitating the fusion of autophagosomes with the CCV. During gene silencing of CLTC, CCVs are unable to fuse with each other, a phenotype also seen when silencing genes involved in macroautophagy/autophagy. MAP1LC3B/LC3B, which is normally observed inside the CCV, is excluded from CCVs in the absence of CLTC. Additionally, this study demonstrates that autophagosome fusion contributes to CCV size as cell starvation and subsequent autophagy induction leads to further CCV expansion. This is CLTC dependent, as the absence of CLTC renders autophagosomes no longer able to contribute to the expansion of the CCV. This investigation provides a functional link between CLTC and autophagy in the context of Coxiella infection and highlights the CCV as an important tool to explore the interactions between these vesicular trafficking pathways.
PTENα regulates mitophagy and maintains mitochondrial quality controlLi, Guoliang; Yang, Jingyi; Yang, Chunyuan; Zhu, Minglu; Jin, Yan; McNutt, Michael A.; Yin, Yuxin
doi: 10.1080/15548627.2018.1489477pmid: 29969932
PTEN plays an important role in tumor suppression, and PTEN family members are involved in multiple biological processes in various subcellular locations. Here we report that PTENα, the first identified PTEN isoform, regulates mitophagy through promotion of PARK2 recruitment to damaged mitochondria. We show that PTENα-deficient mice exhibit accumulation of cardiac mitochondria with structural and functional abnormalities, and PTENα-deficient mouse hearts are more susceptible to injury induced by isoprenaline and ischemia-reperfusion. Mitochondrial clearance by mitophagy is also impaired in PTENα-deficient cardiomyocytes. In addition, we found PTENα physically interacts with the E3 ubiquitin ligase PRKN, which is an important mediator of mitophagy. PTENα binds PRKN through the membrane binding helix in its N-terminus, and promotes PRKN mitochondrial translocation through enhancing PRKN self-association in a phosphatase-independent manner. Loss of PTENα compromises mitochondrial translocation of PRKN and resultant mitophagy following mitochondrial depolarization. We propose that PTENα functions as a mitochondrial quality controller that maintains mitochondrial function and cardiac homeostasis.Abbreviations: BECN1 beclin 1; CCCP carbonyl cyanide m-chlorophenylhydrazone; FBXO7 F-box protein 7; FS fraction shortening; HSPA1L heat shock protein family A (Hsp70) member 1 like; HW: BW heart weight:body weight ratio; I-R ischemia-reperfusion; ISO isoprenaline; MAP1LC3/LC3 microtubule associated protein 1 light chain 3; MBH membrane binding helix; MFN1 mitofusin 1; MFN2 mitofusin 2; Nam nicotinamide; TMRM tetramethylrhodamine ethyl ester; WGA wheat germ agglutinin
Specific autophagy and ESCRT components participate in the unconventional secretion of CFTRNoh, Shin Hye; Gee, Heon Yung; Kim, Yonjung; Piao, He; Kim, Jiyoon; Kang, Chung Min; Lee, Gahyung; Mook-Jung, Inhee; Lee, Yangsin; Cho, Jin Won; Lee, Min Goo
doi: 10.1080/15548627.2018.1489479pmid: 29969945
The most common mutation in cystic fibrosis patients is a phenylalanine deletion at position 508 (ΔF508) in the CFTR (cystic fibrosis transmembrane conductance regulator) gene. This mutation impairs cell-surface trafficking of CFTR. During cellular stress, core-glycosylated CFTRΔF508 is transported to the cell surface from the endoplasmic reticulum (ER) via an unconventional route that bypasses the Golgi. However, the mechanisms for this unconventional secretory pathway of CFTR are not well delineated. Here, we report that components of the macroautophagy/autophagy and ESCRT (endosomal sorting complex required for transport) pathways are involved in unconventional secretion of CFTR. In mammalian cells, we found that autophagic pathways were modulated by conditions that also stimulate unconventional secretion, namely ER stress and an ER-to-Golgi transport blockade. Additionally, we found that knockdown of early autophagy components, ATG5 and ATG7, and treatment with pharmacological autophagy inhibitors, wortmannin and 3-methyladenine, abolished the unconventional secretion of CFTR that had been stimulated by ER stress and an ER-to-Golgi blockade. Interestingly, immunoelectron microscopy revealed that GORASP2/GRASP55, which mediates unconventional CFTR trafficking, is present in multivesicular bodies (MVB) and autophagosomal structures under ER stress conditions. A custom small-interfering RNA screen of mammalian ESCRT proteins that mediate MVB biogenesis showed that silencing of some ESCRTs, including MVB12B, inhibited unconventional CFTRΔF508 secretion. Furthermore, MVB12B overexpression partially rescued cell-surface expression and Cl− channel function of CFTRΔF508. Taken together, these results suggest that components involved in early autophagosome formation and the ESCRT/MVB pathway play a key role in the stress-induced unconventional secretion of CFTR.
Dynamic MTORC1-TFEB feedback signaling regulates hepatic autophagy, steatosis and liver injury in long-term nutrient oversupplyZhang, Hao; Yan, Shengmin; Khambu, Bilon; Ma, Fengguang; Li, Yong; Chen, Xiaoyun; Martina, Jose. A.; Puertollano, Rosa; Li, Yu; Chalasani, Naga; Yin, Xiao-Ming
doi: 10.1080/15548627.2018.1490850pmid: 30044707
Normal metabolism requires a controlled balance between anabolism and catabolism. It is not completely known how this balance can be retained when the level of nutrient supply changes in the long term. We found that in murine liver anabolism, as represented by the phosphorylation of RPS6KB (ribosomal protein S6 kinase), was soon elevated while catabolism, as represented by TFEB (transcription factor EB)-directed gene transcription and lysosomal activities, was downregulated after the administration of a high-fat diet (HFD). Surprisingly, neither the alteration in RPS6KB phosphorylation nor that in TFEB functions was static over the long course of HFD feeding. Instead, the 2 signals exhibited dynamic alterations in opposite directions, which could be explained by the dependence of MTORC1 (MTOR complex 1) activation on TFEB-supported lysosome function and the feedback suppression of TFEB by MTORC1. Disruption of the dynamics by enforced expression of TFEB in HFD-fed mice at the peaks of MTORC1 activation restored lysosome function. Consistently, interference of MTORC1 activation with rapamycin or with a constitutively activated RRAGA mutant at the peak or nadir of MTORC1 oscillation enhanced or reduced the lysosome function, respectively. These treatments also improved or exacerbated hepatic steatosis and liver injury, respectively. Finally, there was a significant inverse correlation between TFEB activation and steatosis severity in the livers of patients with non-alcohol fatty liver diseases, supporting the clinical relevance of TFEB-regulated events. Thus, maintaining catabolic function through feedback mechanisms during enhanced anabolism, which is caused by nutrient oversupply, is important for reducing liver pathology.