Lysosome biogenesis in health and disease

Bajaj, Lakshya; Lotfi, Parisa; Pal, Rituraj; Ronza, Alberto di; Sharma, Jaiprakash; Sardiello, Marco

doi:10.1111/jnc.14564

Cited by 113 publications

(120 citation statements)

References 173 publications

(182 reference statements)

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“…Lysosomes contain more than 50 soluble hydrolytic enzymes that mediate the degradation of macromolecules according to various catabolic programs. Lysosomal enzymes are synthesized at the endoplasmic reticulum (ER) and transferred to the endolysosomal system via the secretory route (1,2). Whereas the post-Golgi trafficking of lysosomal enzymes has been amply characterized (3), the early, pre-Golgi stages of lysosomal enzyme trafficking are only partially understood.…”

Section: Introductionmentioning

confidence: 99%

A CLN6-CLN8 complex recruits lysosomal enzymes at the ER for Golgi transfer

Bajaj

Ronza

Zheng³

et al. 2019

Preprint

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Lysosomal enzymes are synthesized in the endoplasmic reticulum (ER) and transferred to the Golgi complex by interaction with the Batten disease protein CLN8. Here we investigated the relationship of this pathway with CLN6, an ER-associated protein of unknown function that is defective in a different Batten disease subtype. Experiments focused on protein interaction and trafficking identified CLN6 as an obligate component of a CLN6-CLN8 complex (herein referred to as EGRESS: ER-to-Golgi relaying of enzymes of the lysosomal system) which recruits lysosomal enzymes at the ER to promote their Golgi transfer. Simultaneous deficiency of CLN6 and CLN8 did not aggravate mouse pathology compared to the single deficiencies, indicating that the EGRESS complex works as a functional unit. Mutagenesis experiments showed that the second luminal loop of CLN6 is required for the interaction of CLN6 with the enzymes but dispensable for interaction with CLN8, and in vitro and in vivo studies showed that CLN6 deficiency results in inefficient ER export of lysosomal enzymes and diminished levels of the enzymes at the lysosome. These results identify CLN6 and the EGRESS complex as key players in lysosome biogenesis and shed light on the molecular etiology of Batten disease caused by defects in CLN6.

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Section: Introductionmentioning

confidence: 99%

A CLN6-CLN8 complex recruits lysosomal enzymes at the ER for Golgi transfer

Bajaj

Ronza

Zheng³

et al. 2019

Preprint

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“…More recently, the lysosome has been identified as a key metabolic hub, influencing processes as diverse as nutrient sensing, secretion, gene regulation, plasma membrane repair, ion homeostasis, immune responses, and cholesterol transport (Bajaj et al . ). Because of its widespread involvement in numerous fundamental homeostatic processes, it is not surprising that mutations in genes involved in lysosomal biology often result in devastating disease.…”

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confidence: 97%

“…; Bajaj et al . ). TFEB is a cytoplasmic protein that translocates to the nucleus upon phosphorylation and activates the expression of a wide array of lysosomal‐related genes.…”

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confidence: 97%

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Lysosomal storage disorders: pathology within the lysosome and beyond

Kielian

2019

Journal of Neurochemistry

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This Preface introduces the articles of the special issue on “Lysosomal Storage Disorders” in which several recognized experts provide an overview of this research field. Lysosomes were first described in the 1950s and recognized for their role in substrate degradation and recycling. Because lysosomes impact numerous fundamental homeostatic processes, research on lysosomal storage disorders (LSDs) is crucial to advance our understanding of this intriguing organelle. This Special Issue highlights some of the LSDs that impact the central nervous system (CNS) as well as comprehensive overviews of lysosomal biology, CNS metabolism, and sphingolipid biosynthesis and turnover, all of which are critical toward our understanding of normal lysosomal function and how this is perturbed in the context of LSDs. https://onlinelibrary.wiley.com/page/journal/14714159/homepage/virtual_issues.htm. Cover Image for this issue: doi: .

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“…The mechanism that contributes to lysosomal protein down-modulation after L. donovani infection, is elusive. One possible scenario would be a dysregulation of transcription factor EB, which is a master regulator of lysosomal biogenesis that mediates the transcription of many lysosomal hydrolases [62]. Another scenario would be that the lysosomal content is modified via the action of lysosomal exocytosis, which takes place to repair host cell plasma wounding caused by the parasite [63] or by the direct interaction of the parasites’ exo-proteases with lysosomal proteins, leading to protein degradation.…”

Section: Resultsmentioning

confidence: 99%

SILAC-based quantitative proteomics reveals pleiotropic, phenotypic modulation in primary murine macrophages infected with the protozoan pathogenLeishmania donovani

Smirlis

Dingli

Pescher

et al. 2019

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Leishmaniases are major vector-borne tropical diseases responsible for great human morbidity and mortality, caused by protozoan, trypanosomatid parasites of the genus Leishmania. In the mammalian host parasites survive and multiply within mononuclear phagocytes, especially macrophages. However, the underlying mechanisms by which Leishmania spp affect their host, are not fully understood. Herein, proteomic alterations of primary bone marrow-derived, BALB/c macrophages are documented after 72 h of infection with Leishmania donovani insect-stage promastigotes, with the use of a SILAC-based, quantitative proteomics approach. The protocol was optimised by combining strong anion exchange and gel electrophoresis fractionation that displayed similar depth of analysis (>5500 proteins). Our analyses revealed 86 differentially modulated proteins (35 showing increased and 51 decreased abundance) in response to Leishmania donovani infection. The proteomics results were validated by analysing the abundance of selected proteins. Intracellular Leishmania donovani infection led to changes in various host cell biological processes, including primary metabolism and catabolic process, with a significant enrichment in lysosomal organisation. Overall, our analysis allows new technical insight into the challenges of quantitative proteomics applied on primary cells, and establishes the first proteome of bona fide primary macrophages infected ex vivo with Leishmania donovani, revealing new mechanisms acting at the host/pathogen interface.

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Lysosome biogenesis in health and disease

Cited by 113 publications

References 173 publications

A CLN6-CLN8 complex recruits lysosomal enzymes at the ER for Golgi transfer

A CLN6-CLN8 complex recruits lysosomal enzymes at the ER for Golgi transfer

Lysosomal storage disorders: pathology within the lysosome and beyond

SILAC-based quantitative proteomics reveals pleiotropic, phenotypic modulation in primary murine macrophages infected with the protozoan pathogenLeishmania donovani

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