Martinez J et al. (2011) Proc Natl Acad Sci U S A "Microtubule-associated protein 1 light chain 3 alpha (LC3)-associated phagocytosis is required for the efficient clearance of dead cells."

FitzGerald P, Ness R, Almendinger J, Martinez J, Dillon CP, Green DR, Hengartner MO, Oberst A

[Proc Natl Acad Sci U S A, 2011]

The recognition and clearance of dead cells is a process that must occur efficiently to prevent an autoimmune or inflammatory response. Recently, a process was identified wherein the autophagy machinery is recruited to pathogen-containing phagosomes, termed MAPLC3A (LC3)-associated phagocytosis (LAP), which results in optimal degradation of the phagocytosed cargo. Here, we describe the engagement of LAP upon uptake of apoptotic, necrotic, and RIPK3-dependent necrotic cells by macrophages. This process is dependent on some members of the classical autophagy pathway, including Beclin1, ATG5, and ATG7. In contrast, ULK1, despite being required for autophagy, is dispensable for LAP induced by uptake of microbes or dead cells. LAP is required for efficient degradation of the engulfed corpse, and in the absence of LAP, engulfment of dead cells results in increased production of proinflammatory cytokines and decreased production of anti-inflammatory cytokines. LAP is triggered by engagement of the TIM4 receptor by either phosphatidylserine (PtdSer)-displaying dead cells or PtdSer-containing liposomes. Therefore, the consequence of phagocytosis of dead cells is strongly affected by those components of the autophagy pathway involved in LAP.

Morales-Martinez A et al. (2015) J Cell Sci "Inner nuclear membrane protein LEM-2 is required for correct nuclear separation and morphology in C. elegans."

Dobrzynska A, Morales-Martinez A, Askjaer P

[J Cell Sci, 2015]

The inner nuclear membrane proteins emerin and LEMD2 have both overlapping and separate functions in regulation of nuclear organization, gene expression and cell differentiation. We report here that emerin (EMR-1) and LEM domain protein 2 (LEM-2) are expressed in all tissues throughout Caenorhaditis elegans development but their relative distribution differs between cell types. The ratio of EMR-1 to LEM-2 is particularly high in contractile tissues, intermediate in neurons and hypodermis and lowest in intestine and germ line. We find that LEM-2 is recruited earlier than EMR-1 to reforming nuclear envelopes, suggesting the presence of separate mitotic membrane compartments and specific functions of each protein. Concordantly, we observe that nuclei of lem-2 mutant embryos, but not of emr-1 mutants, have reduced nuclear circularity. Finally, we uncover a so-far-unknown role of LEM-2 in nuclear separation and anchoring of microtubule organizing centers.

Martinez BA et al. (2017) J Neurosci "Dysregulation of the mitochondrial unfolded protein response induces non-apoptotic dopaminergic neurodegeneration in C. elegans models of Parkinson's disease."

Caldwell KA, Martinez BA, Stanley SP, Caldwell GA, Gaeta AL, Petersen DA

[J Neurosci, 2017]

Due to environmental insult or innate genetic deficiency, protein folding environments of the mitochondrial matrix are prone to dysregulation, prompting the activation of a specific organellar stress-response mechanism the mitochondrial unfolded protein response (UPR(MT)). In Caenorhabditis elegans, mitochondrial damage leads to nuclear translocation of the ATFS-1 transcription factor to activate the UPR(MT) After short-term acute stress has been mitigated, the UPR(MT) is eventually suppressed to restore homeostasis to C. elegans hermaphrodites. In contrast, and reflective of the more chronic nature of progressive neurodegenerative disorders like Parkinson's disease (PD), here we report the consequences of prolonged, cell-autonomous activation of the UPR(MT) in C. elegans dopaminergic neurons. We reveal that neuronal function and integrity rapidly declines with age, culminating in activity-dependent, non-apoptotic cell death. In a PD-like context wherein transgenic nematodes express the Lewy-body constituent protein, -synuclein (S), we not only find that this protein and its PD-associated disease variants have the capacity to induce the UPR(MT), but also that coexpression of S and ATFS-1-associated dysregulation of the UPR(MT) synergistically potentiate dopaminergic neurotoxicity. This genetic interaction is in parallel to mitophagic pathways dependent on the C. elegansPINK1 homologue, which is necessary for cellular resistance to chronic malfunction of the UPR(MT) Given the increasingly recognized role of mitochondrial quality control in neurodegenerative diseases, these studies illustrate, for the first time, an insidious aspect of mitochondrial signaling, whereby the UPR(MT) pathway, under disease-associated, context-specific dysregulation, exacerbates disruption of dopaminergic neurons in vivo, resulting in neurodegeneration characteristic of PD.SIGNIFICANCE STATEMENTDisruptions or alterations in the activation of pathways which regulate mitochondrial quality control have been linked to neurodegenerative diseases due in part to the central role of mitochondria in metabolism, ROS regulation, and proteostasis. The extent to which these pathways, including the UPR(MT) and mitophagy, are active may predict severity and progression of these disorders as well as sensitivity to compounding stressors. Furthermore, therapeutic strategies which may aim to induce these pathways may benefit from increased study into cellular responses that arise from long term or ectopic stimulation, especially in neuronal compartments. By demonstrating detrimental consequences of prolonged cellular activation of the UPR(MT) we provide evidence that this pathway is not a universally beneficial mechanism, since dysregulation has neurotoxic consequences.

Martinez-Finley EJ et al. (2011) J Toxicol "Revelations from the Nematode Caenorhabditis elegans on the Complex Interplay of Metal Toxicological Mechanisms."

Martinez-Finley EJ, Aschner M

[J Toxicol, 2011]

Metals have been definitively linked to a number of disease states. Due to the widespread existence of metals in our environment from both natural and anthropogenic sources, understanding the mechanisms of their cellular detoxification is of upmost importance. Organisms have evolved cellular detoxification systems including glutathione, metallothioneins, pumps and transporters, and heat shock proteins to regulate intracellular metal levels. The model organism, Caenorhabditis elegans (C. elegans), contains these systems and provides several advantages for deciphering the mechanisms of metal detoxification. This review provides a brief summary of contemporary literature on the various mechanisms involved in the cellular detoxification of metals, specifically, antimony, arsenic, cadmium, copper, manganese, mercury, and depleted uranium using the C. elegans model system for investigation and analysis.

McGhee JD (1987) Biochemistry "Purification and characterization of a carboxylesterase from the intestine of the nematode Caenorhabditis elegans."

McGhee JD

[Biochemistry, 1987]

The major intestinal esterase from the nematode Caenorhabditis elegans has been purified to essential homogeneity. Starting from whole worms, the overall purification is 9000-fold with a 10% recovery of activity. The esterase is a single polypeptide chain of Mr 60,000 and is stoichiometrically inhibited by organophosphates. Substrate preferences and inhibition patterns classify the enzyme as a carboxylesterase (EC 3.1.1.1), but the physiological function is unknown. The sequence of 13 amino acid residues at the esterase N- terminus has been determined. This partial sequence shows a surprisingly high degree of similarity to the N-terminal sequence of two carboxylesterases recently isolated from Drosophila mojavensis [Pen, J., van Beeumen, J., & Beintema, J. J. (1986) Biochem. J. 238, 691-699].

Murakami S et al. (1999) Curr Biol "Life extension and stress resistance in Caenorhabditis elegans modulated by the tkr-1 gene."

Johnson TE, Murakami S

[Curr Biol, 1999]

In this Brief Communication, which appeared in the 14 September 1998 issue of Current Biology, the UV dose was reported erroneously. The dose reported was 20 J/m2 but the actual dose used was 0.4 J/cm2. Also, the gene formally referred to as tkr-1 has since been renamed old-1 (overexpression longevity determination).

Ramos CG et al. (2014) J Bacteriol "Retraction for Ramos et al., MtvR is a global small noncoding regulatory RNA in Burkholderia cenocepacia."

Feliciano JR, da Costa PJ, Ramos CG, Grilo AM, Leitao JH

[J Bacteriol, 2014]

Volume 195, no. 16, p. 35143523, 2013. A number of problems related to images published in this paper have been brought to our attention. Figure 1D contains duplicated images in lanes S and LE, and Fig. 4D and 6B contain images previously published in articles in this journal and in Microbiology and Microbial Pathogenesis, i.e., the following: C. G. Ramos, S. A. Sousa, A. M. Grilo, J. R. Feliciano, and J. H. Leitao, J. Bacteriol. 193:15151526, 2011. doi:10.1128/JB.01374-11. S. A. Sousa, C. G. Ramos, L. M. Moreira, and J. H. Leitao, Microbiology 156:896908, 2010. doi:10.1099/mic.0.035139-0. C. G. Ramos, S. A. Sousa, A. M. Grilo, L. Eberl, and J. H. Leitao, Microb. Pathog. 48:168177, 2010. doi: 10.1016/j.micpath.2010.02.006. Therefore, we retract the paper. We deeply regret this situation and apologize for any inconvenience to the editors and readers of Journal of Bacteriology, Microbial Pathogenesis, and Microbiology.

Nillegoda NB et al. (2015) Nature "Crucial HSP70 co-chaperone complex unlocks metazoan protein disaggregation."

Berynskyy M, Morimoto RI, Bukau B, Stengel F, Kirstein J, Szlachcic A, Arnsburg K, Stank A, Scior A, Nillegoda NB, Gao X, Guilbride DL, Aebersold R, Wade RC, Mayer MP

[Nature, 2015]

Protein aggregates are the hallmark of stressed and ageing cells, and characterize several pathophysiological states. Healthy metazoan cells effectively eliminate intracellular protein aggregates, indicating that efficient disaggregation and/or degradation mechanisms exist. However, metazoans lack the key heat-shock protein disaggregase HSP100 of non-metazoan HSP70-dependent protein disaggregation systems, and the human HSP70 system alone, even with the crucial HSP110 nucleotide exchange factor, has poor disaggregation activity in vitro. This unresolved conundrum is central to protein quality control biology. Here we show that synergic cooperation between complexed J-protein co-chaperones of classes A and B unleashes highly efficient protein disaggregation activity in human and nematode HSP70 systems. Metazoan mixed-class J-protein complexes are transient, involve complementary charged regions conserved in the J-domains and carboxy-terminal domains of each J-protein class, and are flexible with respect to subunit composition. Complex formation allows J-proteins to initiate transient higher order chaperone structures involving HSP70 and interacting nucleotide exchange factors. A network of cooperative class A and B J-protein interactions therefore provides the metazoan HSP70 machinery with powerful, flexible, and finely regulatable disaggregase activity and a further level of regulation crucial for cellular protein quality control.

Miller DM et al. (1992) Worm Breeder's Gazette "unc-4 LacZ Expression in A-Type Motor Neurons"

Miller DM, Niemeyer CJ

[Worm Breeder's Gazette, 1992]

unc-4 LacZ expression in A-type motor neurons David M. Miller and Charles J. Niemeyer, Dept. of Cell Biology, Duke Univ. Medical Ctr, Durham, NC 27710

Jenzer, Celine et al. (2015) International Worm Meeting "Determination of functional specificity of autophagic proteins during phagocytosis of apoptotic cells in embryo."

Largeau, Celine, Legouis, Renaud, Yao, Tianyou, Jenzer, Celine, Liu, Xianghua, Simionato, Elena, Zhou, Zheng

[International Worm Meeting, 2015]

Phagocytosis and autophagy are two lysosome-mediated processes involved in the clearance of extracellular and intracellular components, respectively. These two processes are involved in various human diseases such as cancers. Previously, the laboratory has shown a sequential and specific involvement of autophagic proteins in the autophagic cascade [1,2]. Recent studies have identified the recruitment of autophagic proteins during phagocytosis of apoptotic corpses in the so called LC3-associated phagocytosis (LAP) [3]. LAP is a distinct process from autophagy but it relies on some members of autophagy pathway to allow an efficient degradation of the phagocytosed cargo. The objective of this study is to elucidate the physiological and pathological roles of autophagy in the phagocytosis of apoptotic corpses in Caenorhabditis elegans. Using time-lapse microscopy, electron microscopy and genetic approaches, we analyzed the function of the LC3 homologues, LGG-1 and LGG-2, during this process. In this study, we showed that these proteins are involved in the phagocytosis of apoptotic cells. Indeed, lgg-1 and lgg-2 mutants present an enhanced number of apoptotic cells compared to wild type embryos. Moreover, differences in LGG-1 and LGG-2 expression profile in apoptototic corpses and phagocytic cells demonstrated differential participation of the two proteins. Finally, we characterized the interaction between these autophagic proteins and the machinery of phagosome maturation (HOPS, Rab, ...). Our results suggest complex roles of the C. elegans LC3 homologs in the clearance of apoptotic cells.[1] Manil-Segalen, M. et al. The C. elegans LC3 Acts Downstream of GABARAP to Degrade Autophagosomes by Interacting with the HOPS Subunit VPS39. Dev. Cell 28. 43-55 (2014).[2] Jenzer, C. et al. Human GABARAP can restore autophagosome biogenesis in C. elegans lgg 1 mutant. Autophagy 10. 1868-1872 (2014).[3] Martinez, J. et al. Microtubule-associated protein 1 light chain 3 alpha (LC3)-associated phagocytosis is required for the efficient clearance of dead cells. Proc. Natl. Acad. Sci. U. S. A. 108. 17396-17401 (2011).