Lecture 6: Lysosomes - Structure, Regulation, and Function

Comprehensive vocabulary flashcards generated from lecture notes covering lysosomal components, biogenesis, trafficking, nutrient sensing signaling pathways, membrane repair, lysophagy, and analytical techniques.

Lysosome

The major degradative compartment of eukaryotic cells, characterized by an acidic lumen ($\text{pH} \times 4.5\text{--}6.0$), which orchestrates nutrient sensing, macromolecular breakdown, recycling, repair, and stress adaptation.

Acidic Hydrolases

A group of approximately 60 lumenal enzymes (including proteases, lipases, nucleases, glycosidases, and phosphatases) that digest macromolecules and operate optimally under acidic conditions.

Saposins and Granulins

Lumenal cofactors within the lysosome that assist acidic hydrolases in the breakdown of macromolecules.

V-ATPase

An integral membrane proton pump that hydrolyzes ATP to pump $H^+$ ions into the lysosomal lumen, creating and maintaining its acidic environment.

ClC-7

A lysosomal membrane channel that provides counter-ion transport to help maintain the pH gradient generated by V-ATPase.

LAMPs and LIMPs

Lysosome-Associated Membrane Proteins and Lysosomal Integral Membrane Proteins that serve as key structural integral membrane proteins of the lysosome.

Mannose-6-phosphate (M6P) Receptor Pathway

The primary pathway for delivering soluble lysosomal hydrolases synthesized in the ER and sorted through the Golgi to lysosomes via clathrin-coated vesicles.

I-cell Disease

A condition caused by a defect in GNPT that prevents proper M6P tagging, resulting in the mis-targeting of lysosomal enzymes and their hyper-secretion outside the cell.

Lysosomal Storage Disorders (LSDs)

A class of diseases caused by defects in lysosomal function (e.g., GNPT mutations leading to mucolipidosis II and III) that result in the accumulation of undigested substrates.

mTORC1

Mechanistic target of rapamycin complex 1; a central signaling complex located on the lysosomal membrane that responds to nutrients, growth factors, energy status, and cellular stress to drive cell growth and proliferation.

Rag GTPases

Small GTPases functioning as heterodimers (Rag A/B and Rag C/D) that sense nutrient availability and recruit mTORC1 to the lysosomal surface under high nutrient conditions.

RHEB GTPase

A small GTPase that responds primarily to growth factor signaling and directly activates the kinase activity of mTORC1.

MiT/TFE Transcription Factors

A family of transcription factors (including MITF, TFEB, TFE3, and TFEC) that regulate lysosome biogenesis and autophagy by translocating to the nucleus in response to low nutrients or dephosphorylation.

CLEAR Elements

Coordinated Lysosomal Expression and Regulation DNA sequence elements located in the promoter regions of many lysosomal genes, recognized and bound by MiT/TFE factors.

Kinesin (Lysosomal Transport)

A motor protein that mediates anterograde (peripheral) movement of lysosomes along microtubules.

Dynein (Lysosomal Transport)

A motor protein complex that mediates retrograde (perinuclear) movement and clustering of lysosomes along microtubules.

ESCRT Pathway (Lysosomal Repair)

A calcium-dependent, rapid membrane repair mechanism that restores lysosomal integrity through inward constriction of damaged membrane edges.

PITT Pathway

Phosphoinositide-dependent membrane tethering pathway that coordinates rapid lipid transfer between the ER and lysosome to repair damaged lysosomal membranes.

Lysophagy

The selective autophagic degradation of damaged lysosomes that occurs when membrane damage exceeds cellular repair capacity.

Galectins (Lysophagy)

Cytosolic proteins that bind to exposed glycosylated lysosomal lumenal proteins upon membrane rupture to signal ubiquitin ligase recruitment and initiate lysophagy.

Autophagic Lysosome Reformation (ALR)

The process of restoring functional lysosome populations following autophagy through $PtdIns(4,5)P_2$ accumulation, kinesin-mediated tubulation, and proto-lysosome budding.

TBC1D15

A protein that acts alongside ATG8 proteins and LIMP2 to provide a scaffold for ALR machinery, promoting lysosomal tubule formation and regeneration.

LYTACs

Lysosome targeting chimeras; a targeted degradation technology that utilizes lysosomal degradation pathways to selectively degrade target proteins.

Magnetic Isolation (Lysosomes)

An isolation strategy (such as NANOLYSE) using endocytosed iron dextran particles (FeDex) or superparamagnetic iron oxide nanoparticles (SPIONs) to pull out intact lysosomes using a magnet.