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The lysosome as an imperative regulator of autophagy and cell death

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Abstract

Lysosomes are single membrane-bound organelles containing acid hydrolases responsible for the degradation of cellular cargo and maintenance of cellular homeostasis. Lysosomes could originate from pre-existing endolysosomes or autolysosomes, acting as a critical juncture between autophagy and endocytosis. Stress that triggers lysosomal membrane permeabilization can be altered by ESCRT complexes; however, irreparable damage to the membrane results in the induction of a selective lysosomal degradation pathway, specifically lysophagy. Lysosomes play an indispensable role in different types of autophagy, including microautophagy, macroautophagy, and chaperone-mediated autophagy, and various cell death pathways such as lysosomal cell death, apoptotic cell death, and autophagic cell death. In this review, we discuss lysosomal reformation, maintenance, and degradation pathways following the involvement of the lysosome in autophagy and cell death, which are related to several pathophysiological conditions observed in humans.

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Fig. 1

source membrane derived from Golgi and ER. The phagophore is then elongated to form the autophagosome, which fuses with the lysosome to form the autolysosome. Subsequently, tubulation events occur with the help of the KIF5B and VPS34-UVRAG complex. PIP5K1B helps in converting PI(4)P to PI(4,5)P2. Then the budded tubule is fragmented with the help of DNM2 and PIP5K1A to form the protolysosome. The resultant protolysosomes undergo maturation to form the functional lysosomes, which are again available for the fusion events and degradation pathways

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Abbreviations

TFEB:

Transcription factor EB

mTORC1:

Mechanistic target of rapamycin complex 1

VAMP7:

Vesicle associated membrane Protein 7

VAMP8:

Vesicle associated membrane Protein 8

NSF:

N-Ethylmaleimide sensitive factor

SNAP:

Soluble NSF attachment proteins

RILP:

Rab-interacting lysosomal protein

p70S6K1:

P70-S6 kinase 1

LAMP1:

Lysosomal-associated membrane protein 1

ATF4:

Activating transcription factor 4

WASP:

Wiskott-Aldrich syndrome protein

PIP5K1B:

PtdIns(4)P-5-kinase-1-baeta

KIF5B:

Kinesin family member 5B

UVRAG:

UV radiation resistance-associated gene

DNM2:

Dynamin2

CHMP4B:

Charged multivesicular body protein 4B

TRIM16:

Tripartite motif containing 16

UBE2QL1:

Ubiquitin conjugating enzyme E2 Q family like 1

ULK1:

Unc-51 like autophagy activating kinase-1

FIP200:

Focal adhesion kinase family interacting protein of 200 kDa

BECN1:

Beclin1

WIPI1:

WD repeat domain, phosphoinositide interacting 1

NRBF2:

Nuclear receptor-binding factor 2

STX-17:

Syntaxin-17

TECPR1:

Tectonin beta-propeller repeat containing 1

Hsc70:

Heat shock cognate 71 kDa protein

Hsp40:

Heat shock protein of 40 kDa

hip:

Hsc70 interacting protein

hop:

Hsc70-hsp90 organizer protein

Hsp90:

Heat shock protein of 90 kDa

bag-1:

Bcl2-associated athanogene-1

caspase:

Cysteine-dependent aspartate-directed proteases

LIMP2:

Lysosomal integral membrane protein type-2

Apaf1:

Apoptotic protease-activating factor 1

DRAM1:

DNA damage-regulated autophagy modulator

DAPK1:

Death-associated protein kinase 1

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Acknowledgements

KKM is highly acknowledged by the Government of India, Ministry of Science & Technology, Department of Science and Technology (No. DST/INSPIRE Fellowship/2017/IF170344). Research support was partly provided by the Science and Engineering Research Board (SERB) [EMR/2016/001246], Department of Science and Technology.

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Mahapatra, K.K., Mishra, S.R., Behera, B.P. et al. The lysosome as an imperative regulator of autophagy and cell death. Cell. Mol. Life Sci. 78, 7435–7449 (2021). https://doi.org/10.1007/s00018-021-03988-3

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