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Secretory lysosomes

Key Points

  • Secretory lysosomes are dual-function organelles in that they are used as both the lysosome (for degradation) and for storage of secretory proteins of the cell. These specialized organelles are found in a small set of cells, most of which are derived from the haematopoietic lineage. There are a few exceptions, which include melanocytes and renal tubular cells. Secretory lysosomes have a central role in the immune system as many of the effector functions of these cells involve release of their secretory product, for example, the cytolytic machinery (such as perforin and granzymes) of cytotoxic T cells.

  • Secretory lysosomes share many features with both conventional lysosomes and secretory granules, such as structure and content. However, these organelles have unique features, one of which is sorting pathways. Recent data has uncovered several unique protein-sorting pathways, which are used only in cells with secretory lysosomes.

  • Several genetic disorders, including Hermansky–Pudlak, Chediak–Higashi and Griscelli's sydromes, which are characterized by immunodeficiency, impaired platelet synthesis and hypopigmentation, are the result of impaired secretory lysosome function. Work on these disorders and their mouse models has provided valuable insight into aspects of secretory-lysosome function.

  • The mechanism of secretion of these organelles has been partly identified, mainly through work on these genetic diseases, each of which seems to be defective in different steps of secretory lysosome biogenesis or secretion. Among these gene products are Rab proteins and their effectors. This work is also important due to the recent revelation that conventional lysosomes are also capable of secretion, which blurs the distinction between the two populations of lysosomes. However, it is now apparent that secretory lysosomes use some unique components in their secretion machinery.

  • Future work will no doubt uncover how these unique organelles have evolved to become a modified lysosome with specialized secretory mechanisms.

Abstract

Regulated secretion of stored secretory products is important in many cell types. In contrast to professional secretory cells, which store their secretory products in specialized secretory granules, some secretory cells store their secretory proteins in a dual-function organelle, called a secretory lysosome. Functionally, secretory lysosomes are unusual in that they serve both as a degradative and as a secretory compartment. Recent work shows that cells with secretory lysosomes use new sorting and secretory pathways. The importance of these organelles is highlighted by several genetic diseases, in which immune function and pigmentation — two processes that normally involve secretory lysosomes — are impaired.

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Figure 1: Secretory versus endocytic pathways.
Figure 2: Lysosomal contents in cells with conventional lysosomes, secretory granules and secretory lysosomes.
Figure 3: Sorting pathways to the secretory lysosome.
Figure 4: Differential sorting of Fas ligand in cells with and without secretory lysosomes.
Figure 5: Secretion of the secretory lysosome.

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Correspondence to Gillian M. Griffiths.

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DATABASES

LocusLink:

ashen

gunmetal

MyoVa

Rab 3a

Rab27a

Rab geranylgeranyltransferase

 OMIM:

Chediak–Higashi syndrome

Griscelli's syndrome

Hermansky–Pudlak syndrome

 Swiss-Prot:

CD63

CD86

CTLA-4

FasL

GIPC

gp75

granzyme A

LAMP-1

LAMP-2

Lyst

melanophilin

P-Selectin

perforin

Rab3a

Rab3d

Rab37

Rab38

RILP

SCAMP

SNAP-23

synaptotagmin VII

syntaxin 3

syntaxin 4

SytII

SytIII

SytV

VAMP2

VAMP7

Glossary

HAEMATOPOIETIC LINEAGE

The developmental series of cells that are derived from haematopoietic stem cells, which produce blood cells.

MELANOCYTE

A type of pigmented cell that can synthesize and store melanin in melanosomes.

LYSOSOMAL HYDROLASE

A soluble enzyme that is found in lysosomes that are involved in the hydrolytic breakdown of macromolecules. These include proteases, lipases and glycosidases.

CYTOTOXIC T CELL

(CTL). A T cell that can kill other cells. These are important in host defence against most viral pathogens.

NATURAL KILLER CELL

A class of lymphocyte that is crucial in the innate immune response. These exert a cytotoxic activity on target cells (such as virus-infected cells) that is enhanced by cytokines, such as interferons.

MACROPHAGE

Any cell of the mononuclear phagocyte system that is characterized by its ability to phagocytose foreign particulate and colloidal material.

DENDRITIC CELL

A professional antigen-presenting cell that is found in T-cell areas of lymphoid tissues, and also as a minor cellular component in most tissues. These have a branched or dendritic morphology and are the most potent stimulators of T-cell responses.

B CELL

A lymphocyte that develops in the bone marrow and produces antibody.

T CELL

A lymphocyte that develops primarily in the thymus and is important for the regulation and development of immune responses.

PLATELET

The smallest blood cell, which is important in haemostasis and blood coagulation.

BASOPHIL

A polymorphonuclear phagocytic leukocyte of the myeloid series.

MAST CELL

A type of leukocyte of the granulocyte subclass.

NEUTROPHIL

A phagocytic cell of the myeloid lineage that has an important role in the inflammatory response, and undergoes chemotaxis towards sites of infection or wounding.

PHAGOSOME

Large particles, such as bacteria, are engulfed by phagocytosis and are transported to phagosomes. Phagosomal and endosomal pathways undergo interconnected maturation and merge before fusion with lysosomes. Mycobacterium tuberculosis can modify this pathway and prevent phagosomal maturation.

DEFENSIN

An antimicrobial peptide that is secreted by Paneth cells in the villus crypt.

AZUROCIDIN

A glycoprotein that is produced in neutrophils, and has broad-spectrum antimicrobial activity and chemotactic activity towards monocytes.

AUTOPHAGY

A complete intracellular mechanism, which leads to bulk protein degradation, and involves the sequestering of cytosol into vesicles for delivery to a degradative organelle.

ADAPTOR COMPLEX

(refers to AP1, AP2, AP3 and AP4). A heterotetrameric cytosolic complex that is involved in recruitment of cargo and accessory proteins to vesicles that are involved in transport.

PDZ DOMAIN

A domain that is found in many cytosolic proteins and is named after the founding members of this protein family (Psd-95, discs-large and ZO-1). This is an 90-residue structural motif, which regulates protein–protein interactions, largely by binding to a specific tripeptide motif.

KINESIN FAMILY

The kinesin superfamily contains a range of motor proteins that have similarities to classical 'vesicle' kinesin in the conserved microtubule-binding motor region. The motor can be at the amino-terminus, in the middle, or at the carboxyl terminus (in which case the protein usually migrates to the minus end of the microtubule).

SNARE FAMILY

(soluble N-ethylmaleimide-sensitive factor attachment protein receptor). A family of membrane-tethered coiled-coil proteins that regulate fusion reactions and target specificity in the vacuolar system. They can be divided into v-SNAREs and t-SNAREs on the basis of their localization (vesicle and target, respectively), or into Q-SNAREs and R-SNAREs on the basis of a highly conserved amino acid (Gln and Arg, respectively).

RAB FAMILY

Rab proteins form the largest subfamily of small GTPases of the Ras superfamily. They regulate budding, tethering, fusion and motility at various sites within cells.

PRENYLATION

The post-translational modification of proteins by the enzymatic addition of prenyl moieties, which allows membrane attachment.

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Blott, E., Griffiths, G. Secretory lysosomes. Nat Rev Mol Cell Biol 3, 122–131 (2002). https://doi.org/10.1038/nrm732

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