Chaperone-assisted selective autophagy is a cellular process for the selective,

ubiquitin Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Fo ...

-dependent degradation of chaperone-bound

proteins Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

lysosomes A lysosome () is a membrane-bound organelle found in many animal cells. They are spherical vesicles that contain hydrolytic enzymes that can break down many kinds of biomolecules. A lysosome has a specific composition, of both its membrane prote ...

Autophagy Autophagy (or autophagocytosis; from the Ancient Greek , , meaning "self-devouring" and , , meaning "hollow") is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-dependent re ...

(Greek: ‘self-eating’) was initially identified as a catabolic process for the unselective degradation of cellular content in lysosomes under starvation conditions. However, autophagy also comprises selective degradation pathways, which depend on

conjugation to initiate sorting to lysosomes. In the case of chaperone-assisted selective autophagy, dysfunctional, nonnative proteins are recognized by molecular chaperones and become ubiquitinated by chaperone-associated

ligases. The ubiquitinated proteins are enclosed in autophagosomes, which eventually fuse with lysosomes, leading to the degradation of the dysfunctional proteins. Chaperone-assisted selective autophagy is a vital part of the cellular protein quality control system. It is essential for protein homeostasis (

proteostasis Proteostasis is the dynamic regulation of a balanced, functional proteome. The proteostasis network includes competing and integrated biological pathways within cells that control the biogenesis, folding, trafficking, and degradation of proteins p ...

) in

neurons A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. N ...

and in mechanically strained cells and tissues such as

skeletal muscle Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of muscl ...

heart The heart is a muscular organ in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as carbon dioxide t ...

and

lung The lungs are the primary organs of the respiratory system in humans and most other animals, including some snails and a small number of fish. In mammals and most other vertebrates, two lungs are located near the backbone on either side of t ...

Components and mechanism

The chaperone-assisted selective autophagy complex comprises the molecular chaperones

HSPA8 Heat shock 70 kDa protein 8 also known as heat shock cognate 71 kDa protein or Hsc70 or Hsp73 is a heat shock protein that in humans is encoded by the ''HSPA8'' gene on chromosome 11. As a member of the heat shock protein 70 family and a chaperon ...

and

HSPB8 Heat shock protein beta-8 is a protein that in humans is encoded by the ''HSPB8'' gene. Interactions HSPB8 has been shown to interact with: * HSPB2, and * Hsp27. Clinical importance Mutations in this gene have been associated with an autosom ...

, and the cochaperones

BAG3 BAG family molecular chaperone regulator 3 is a protein that in humans is encoded by the ''BAG3'' gene. BAG3 is involved in chaperone-assisted selective autophagy. Function BAG proteins compete with Hip-1 for binding to the Hsc70/Hsp70 ATPase ...

and

STUB1 STUB1 (STIP1 homology and U-Box containing protein 1) is a human gene that codes for the protein CHIP (C terminus of HSC70-Interacting Protein). Function The CHIP protein encoded by this gene binds to and inhibits the ATPase activity of the cha ...

. BAG3 facilitates the cooperation of HSPA8 and HSPB8 during the recognition of nonnative client proteins. STUB1 mediates the

ubiquitination Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Fo ...

of the chaperone-bound client, which induces the recruitment of the autophagic ubiquitin adaptor

SQSTM1 Sequestosome-1 is a protein that in humans is encoded by the ''SQSTM1'' gene. Also known as the ubiquitin-binding protein p62, it is an autophagosome cargo protein that targets other proteins that bind to it for selective autophagy. By interacti ...

. The adaptor simultaneously interacts with the ubiquitinated client and autophagosome membrane precursors, thereby inducing the autophagic engulfment of the client. Autophagosome formation during chaperone-assisted selective autophagy depends on an interaction of

with

SYNPO2 Myopodin protein, also called Synaptopodin-2 is a protein that in humans is encoded by the ''SYNPO2'' gene. Myopodin is expressed in cardiac, smooth muscle and skeletal muscle, and localizes to Z-disc structures. Structure Myopodin is a 117.4 ...

, which triggers the cooperation with a

VPS18 Vacuolar protein sorting-associated protein 18 homolog is a protein that in humans is encoded by the ''VPS18'' gene. Function Vesicle mediated protein sorting plays an important role in segregation of intracellular molecules into distinct orga ...

-containing protein complex that mediates the fusion of autophagosome membrane precursors. The formed autophagosomes finally fuse with lysosomes, resulting in client degradation.

Clients and physiological role

Proteins that are degraded by chaperone-assisted selective autophagy include pathogenic forms of the

Huntingtin Huntingtin (Htt) is the protein coded for in humans by the ''HTT'' gene, also known as the ''IT15'' ("interesting transcript 15") gene. Mutated ''HTT'' is the cause of Huntington's disease (HD), and has been investigated for this role and also for ...

protein, which cause

Huntington's disease Huntington's disease (HD), also known as Huntington's chorea, is a neurodegenerative disease that is mostly inherited. The earliest symptoms are often subtle problems with mood or mental abilities. A general lack of coordination and an unst ...

. Furthermore, the expression of the cochaperone BAG3 is upregulated in aged neuronal cells, which correlates with an increased necessity to dispose oxidatively damaged proteins through autophagy. Chaperone-assisted selective autophagy is thus essential for

. In mechanically strained cells and tissues, chaperone-assisted selective autophagy mediates the degradation of the

actin Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of over ...

-crosslinking protein

filamin Filamins are a class of proteins that hold two actin filaments at large angles. Filamin protein in mammals is made up of an actin-binding domain at its N-terminus that is followed by 24 immunoglobulin-like repeat modules of roughly 95 amino acids. ...

. Mechanical tension results in unfolding of filamin, leading to recognition by the chaperone complex and to the autophagic degradation of damaged filamin. This is a prerequisite for the maintenance of the

cytoskeleton in mechanically strained cells and tissues. Impairment of chaperone-assisted selective autophagy in patients and animal models causes

muscle dystrophy Muscular dystrophies (MD) are a genetically and clinically heterogeneous group of rare neuromuscular diseases that cause progressive weakness and breakdown of skeletal muscles over time. The disorders differ as to which muscles are primarily affe ...

and

cardiomyopathy Cardiomyopathy is a group of diseases that affect the heart muscle. Early on there may be few or no symptoms. As the disease worsens, shortness of breath, feeling tired, and swelling of the legs may occur, due to the onset of heart failure. A ...

References

{{reflist Cell biology