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PRKAA2, MTOR, and TFEB in the regulation of lysosomal damage response and autophagy

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Abstract

Lysosomes function as critical signaling hubs that govern essential enzyme complexes. LGALS proteins (LGALS3, LGALS8, and LGALS9) are integral to the endomembrane damage response. If ESCRT fails to rectify damage, LGALS-mediated ubiquitination occurs, recruiting autophagy receptors (CALCOCO2, TRIM16, and SQSTM1) and VCP/p97 complex containing UBXN6, PLAA, and YOD1, initiating selective autophagy. Lysosome replenishment through biogenesis is regulated by TFEB. LGALS3 interacts with TFRC and TRIM16, aiding ESCRT-mediated repair and autophagy-mediated removal of damaged lysosomes. LGALS8 inhibits MTOR and activates TFEB for ATG and lysosomal gene transcription. LGALS9 inhibits USP9X, activates PRKAA2, MAP3K7, ubiquitination, and autophagy. Conjugation of ATG8 to single membranes (CASM) initiates damage repair mediated by ATP6V1A, ATG16L1, ATG12, ATG5, ATG3, and TECPR1. ATG8ylation or CASM activates the MERIT system (ESCRT-mediated repair, autophagy-mediated clearance, MCOLN1 activation, Ca2+ release, RRAG-GTPase regulation, MTOR modulation, TFEB activation, and activation of GTPase IRGM). Annexins ANAX1 and ANAX2 aid damage repair. Stress granules stabilize damaged membranes, recruiting FLCN-FNIP1/2, G3BP1, and NUFIP1 to inhibit MTOR and activate TFEB. Lysosomes coordinate the synergistic response to endomembrane damage and are vital for innate and adaptive immunity. Future research should unveil the collaborative actions of ATG proteins, LGALSs, TRIMs, autophagy receptors, and lysosomal proteins in lysosomal damage response.

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Abbreviations

ACTR2/ACTR3:

Actin-related protein 2/actin-related protein 3

AGFG1:

ArfGAP with FG repeats 1

ALG2:

ALG2 alpha-1,3/1,6-mannosyltransferase

ARL8B:

ADP ribosylation factor like GTPase 8B

ATG:

Autophagy related

ATG16L1:

Autophagy-related 16 like 1

ATG3:

Autophagy-related 3

ATG7:

Autophagy-related 7

ATXN3:

Ataxin 3

BECN1:

Beclin 1

CASM:

Conjugation of ATG8 to single membranes

CALCOCO2:

Calcium binding and coiled-coil domain 2

C. elegans :

Caenorhabditis elegans

CNN2:

Calponin 2

CRD:

Carbohydrate recognition domain

DEPTOR:

DEP domain containing MTOR interacting protein

DYSF:

Dysferlin

EIF2A:

Eukaryotic translation initiation factor 2A

EIF4A3:

Eukaryotic translation initiation factor 4A3

EIF2AK2:

Eukaryotic translation initiation factor 2 alpha kinase 2

ERES:

Endoplasmic reticulum exit sites

ESCRT:

Endosomal sorting complex required for transport

FBD:

FIP200-binding domain

FLCN:

Folliculin

FNIP1:

Folliculin interacting protein 1

HSPB1:

Heat shock protein family B (small) member 1

GAP:

GTPase-activating protein

GBP1:

Guanylate binding protein 1

G3BP1:

G3BP stress granule assembly factor 1

GSK3B:

Glycogen synthase kinase 3 beta

IAV:

Influenza A virus

IRGM:

Immunity-related GTPase M

ISR:

Integrated stress response

KD:

Knockdown

KO:

Knockout

LAMP1:

Lysosomal-associated membrane protein 1

LAMP2:

Lysosomal-associated membrane protein 2

LGALS:

Galectin

LGALS3:

Galectin 3

LGALS8:

Galectin 8

LGALS9:

Galectin 9

LAP:

LC3-associated phagocytosis

LIR:

LC3-interacting region

LLOMe:

L-leucyl-l-leucine, methyl ester, monohydrochloride

LMP:

Lysosomal membrane permeabilization

LRRK2:

Leucine-rich repeat kinase 2

MAP1LC3B:

Microtubule-associated protein 1 light chain 3 beta

MAP3K7:

Mitogen-activated protein kinase kinase kinase 7

MEFs:

Mouse embryonic fibroblasts

MCOLN1:

Mucolipin TRP cation channel 1

MTOR/mTOR:

Mechanistic target of rapamycin kinase

M. tb :

Mycobacterium tuberculosis

NUFIP2:

Nuclear FMR1 interacting protein 2

ORF3a:

Open reading frame 3a

OSBP:

Oxysterol-binding protein

ORP:

Oxysterol-binding protein (OSBP)-related protein

PRKN:

Parkin

PD:

Parkinson’s disease

PDCD6IP:

Programmed cell death 6 interacting protein

PI4K2A:

Phosphatidylinositol 4-kinase type 2 alpha

PI3K:

Phosphatidylinositol-3-kinase

PICALM:

Phosphatidylinositol-binding clathrin assembly protein

PITT:

Phosphoinositide-initiated membrane tethering and lipid transport

PLAA:

Phospholipase A2 activating protein

PPP3CB:

Protein phosphatase 3 catalytic subunit beta

PRKAA2/AMPK:

Protein kinase AMP-activated catalytic subunit alpha 2/AMP-activated protein kinase

PRKAG1:

Protein kinase AMP-activated non-catalytic subunit gamma 1

PRKDC:

Protein kinase, DNA-activated, catalytic subunit

PTP4A2:

Protein tyrosine phosphatase 4A2

PE:

Phosphatidyl ethanol amine

PS:

Phosphatidyl serine

R239:

Arginine 239

R65:

Arginine 65

RAB8A:

RAB8A, member RAS oncogene family

RAPTOR:

Regulatory-associated protein of MTOR complex 1

RB1CC1:

RB1 inducible coiled-coil 1

RRAG:

Ras-related GTP binding

SARS-CoV-2:

Severe acute respiratory syndrome coronavirus 2

SEC31A:

SEC31 homolog A, COPII coat complex component

COPII:

coat complex component

SKP1-CUL1-FBXO27:

S-phase kinase associated protein 1-cullin 1-F-box protein 27

SLC38A9:

Solute carrier family 38 member 9

SM:

Sphingomyelin

SQSTM1/p62:

Sequestosome 1

STING1:

Stimulator of interferon response cGAMP interactor 1

SGs:

Stress granules

TFEB:

Transcription factor EB

TECPR1:

Tectonin beta-propeller repeat containing 1

TFRC:

Transferrin receptor

TFE3:

Transcription factor E3

TRIM16:

Tripartite motif containing 16

TSG101:

Tumor susceptibility 101

OSBPL11:

Cholesterol-binding protein oxysterol-binding protein 11

Ub:

Ubiquitin

UBE2QL1:

Ubiquitin-conjugating enzyme E2 Q family like 1

UBXN6:

UBX domain protein 6

ULK1:

Unc-51-like autophagy-activating kinase 1

USP9X:

Ubiquitin-specific peptidase 9 X-linked

VAPA/B:

VAMP-associated protein A/B

VCP:

Valosin containing protein

VPS4B:

Vacuolar protein sorting 4 homolog B

WIPI2:

WD repeat domain, phosphoinositide interacting 2

WT:

Wild type

YOD1:

YOD1 deubiquitinase

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  1. Quantlase Imaging Laboratory, Quantlase Lab LLC, Unit 1-8, Masdar City, Abu Dhabi, UAE

    Mohd Shariq, Mohammad Firoz Khan, Reshmi Raj, Nuzhat Ahsan & Pramod Kumar

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M.S. and MFK conceptualized the project. M.S reviewed the literature. M.S. and MFK wrote the manuscript. M. S designed and created schematic representations. M.S., MFK, RR, NA, and P.K edited the manuscript.

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Shariq, M., Khan, M.F., Raj, R. et al. PRKAA2, MTOR, and TFEB in the regulation of lysosomal damage response and autophagy. J Mol Med 102, 287–311 (2024). https://doi.org/10.1007/s00109-023-02411-7

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