When the capacity of the proteosome to degrade misfolded proteins is limited, the alternate route to eliminate denatured proteins is via forming aggresomes - a process known as aggrephagy. Aggresome formation starts with ubiquitination of misfolded proteins following transport to the microtubule-organizing center (MTOC) with the help of dynein motor proteins. At the MTOC the cargo is encapsulated with intermediate filament proteins to result in the aggresome. Subsequently, this aggresome recruits chaperones that result in its autophagic elimination (Garcia Mata R et al. 2002).
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Boyault C, Zhang Y, Fritah S, Caron C, Gilquin B, Kwon SH, Garrido C, Yao TP, Vourc'h C, Matthias P, Khochbin S.; ''HDAC6 controls major cell response pathways to cytotoxic accumulation of protein aggregates.''; PubMedEurope PMCScholia
Kawaguchi Y, Kovacs JJ, McLaurin A, Vance JM, Ito A, Yao TP.; ''The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress.''; PubMedEurope PMCScholia
GarcÃa-Mata R, Bebök Z, Sorscher EJ, Sztul ES.; ''Characterization and dynamics of aggresome formation by a cytosolic GFP-chimera.''; PubMedEurope PMCScholia
Johnston JA, Ward CL, Kopito RR.; ''Aggresomes: a cellular response to misfolded proteins.''; PubMedEurope PMCScholia
Lam HC, Cloonan SM, Bhashyam AR, Haspel JA, Singh A, Sathirapongsasuti JF, Cervo M, Yao H, Chung AL, Mizumura K, An CH, Shan B, Franks JM, Haley KJ, Owen CA, Tesfaigzi Y, Washko GR, Quackenbush J, Silverman EK, Rahman I, Kim HP, Mahmood A, Biswal SS, Ryter SW, Choi AM.; ''Histone deacetylase 6-mediated selective autophagy regulates COPD-associated cilia dysfunction.''; PubMedEurope PMCScholia
Kim JI, Kim J, Jang HS, Noh MR, Lipschutz JH, Park KM.; ''Reduction of oxidative stress during recovery accelerates normalization of primary cilia length that is altered after ischemic injury in murine kidneys.''; PubMedEurope PMCScholia
Hubbert C, Guardiola A, Shao R, Kawaguchi Y, Ito A, Nixon A, Yoshida M, Wang XF, Yao TP.; ''HDAC6 is a microtubule-associated deacetylase.''; PubMedEurope PMCScholia
Hofmann RM, Pickart CM.; ''Noncanonical MMS2-encoded ubiquitin-conjugating enzyme functions in assembly of novel polyubiquitin chains for DNA repair.''; PubMedEurope PMCScholia
Olzmann JA, Li L, Chudaev MV, Chen J, Perez FA, Palmiter RD, Chin LS.; ''Parkin-mediated K63-linked polyubiquitination targets misfolded DJ-1 to aggresomes via binding to HDAC6.''; PubMedEurope PMCScholia
Garcia-Mata R, Gao YS, Sztul E.; ''Hassles with taking out the garbage: aggravating aggresomes.''; PubMedEurope PMCScholia
Accumulation of excessive reactive oxygen species (ROS) within cells results in oxidative stress. This stress can trigger proteins misfolding and make them dysfunctional. Cilia proteins are damaged when subjected to oxidative stress and may be targeted to the autophagy machinery. This results in the shortening of the cilium (Lam HC et al. 2013, Kim JI et al. 2013). Experiments leading to this finding were performed in mice.
Cellular stress factors damage several cilia proteins and result in their misfolding. These misfolded proteins are translocated into the cytosol of the cell where they are ubiquitinated and eliminated (Lam HC et al. 2013). Confirmatory experiments were performed in mice.
Ubiquitination is the covalent attachment of ubiquitin molecules to substrate proteins with three enzymatic steps - E1 ubiquitin activation, E2 ubiquitin conjugation and E3 ubiquitin protein ligase. UBE2V1 and UBE2N are E2 ubiquitin-conjugating enzymes that form a complex and bind ubiquitin molecules at K63. This leads to the additional binding of ubiquitin entities and formation of a polyubiquitin chain (Hofmann RM et al. 1999). Experiments confirming this finding were performed in yeast cells.
Ubiquitination is the covalent attachment of ubiquitin molecules to substrate proteins with three enzymatic steps - E1 ubiquitin activation, E2 ubiquitin conjugation and E3 ubiquitin protein ligase. UBE2V1 and UBE2N are E2 ubiquitin-conjugating enzymes that form a complex and bind ubiquitin molecules at K63. Consequently, the E3 ligase PRKN (Parkin) binds this complex and facilitates the addition of more ubiquitin molecules. (Olzmann JA et al. 2007).
Stress factors damage and misfold cilia proteins, which are then translocated to the cytosol. Here, they are ubiquitinated via the UBE2N:UBE2V1:Parkin complex. The E3 ligase Parkin recruits the misfolded proteins to the E2 ubiquitin conjugation complex. This results in the polyubiquitination of misfolded proteins targeting them to degradation (Olzmann JA et al. 2007).
Misfolded proteins from cellular stress are destined for degradation via ubiquitination. The E2 ubiquitin conjugating enzymes UBE2N/UBE2V1 and E3 ligase enzyme Parkin recruit and tag multiple K63-linked ubiquitin molecules to the misfolded proteins. Subsequently, the polyubiquitinated proteins dissociate from the E2/E3 system and are driven to degradation (Olzmann JA et al. 2007).
Misfolded proteins in the cytosol are tagged with ubiquitin molecules via the E2 UBE2N/UBE2V1 conjugation complex and E3 ligase Parkin. Misfolded proteins bind Parkin and subsequently Parkin transfers ubiquitin from E2 complex to the proteins (Olzmann JA et al. 2007).
Misfolded proteins in the cytosol are targeted to degradation via ubiquitination. The E2 UBE2N/UBE2V1 and E3 ligase ubiquitination system recruits and transfers ubiquitin molecules to misfolded proteins. The E3 ligase Parkin tags the proteins with multiple K63-linked ubiquitin molecules (Olzmann JA et al. 2007).
When the proteasome machinery is deregulated, misfolded proteins are eliminated by forming aggresomes. To this end, poly-ubiquitinated misfolded proteins bind to a complex comprising of Transitional endoplasmic reticulum ATPase (VCP), Histone deacetylase 6 (HDAC6), Heat shock protein HSP 90 (HSP90) and Heat shock factor protein 1 (HSF1). HDAC6 in the complex interacts with the ubiquitin molecules in the misfolded proteins. Following this binding event, this complex starts dissociating (Boyault C et al. 2007).
Histone deacetylase 6 (HDAC6) plays a key role in the removal of misfolded proteins when the proteosome system is dysregulated. HDAC6 associates with poly-ubiquitinated misfolded proteins and also to the dynein motor system. Subsequently, this complex of HDAC6,misfolded proteins and dynein motor form aggresomes (Kawaguchi Y et al. 2003).
Histone deacetylase 6 (HDAC6) appears to be a master regulator of the cell protective response to cytotoxic protein aggregate formation (Boyault et al. 2007).
Misfolded proteins are transported from the microtubule to the microtubule-organizing center (MTOC) in a dynein-mediated mechanism. Dynein motors carry the cargo along the microtubules from the plus end to the minus end (Garcia Mata R et al. 1999). Confirmatory experiments were performed in grivet cell lines.
Histone deacetylase 6 (HDAC6) binds misfolded proteins destined to form aggresomes and subsequently delivers this to dynein motor proteins. HDAC6 can also bind to microtubules thereby anchoring the misfolded proteins and the dynein motor to the microtubule (Hubbert C et al. 2002). Following this, the dynein motors traverse the microtubule to reach the microtubule-organizing center (MTOC).
Dynein motor complex drives the multi-ubiquitinated misfolded proteins along the microtubule towards the microtubule organizing center. Here, intermediate filament proteins such as vimentin (VIM) are redistributed to ensheath misfolded proteins to form the aggresome (Johnston JA et al. 1998). Subsequently, the aggresome is removed with the help of autophagy machinery.
Misfolded proteins are transformed into aggresomes at the microtubule organizing center. Dynein motor proteins facilitate the transport of misfolded proteins along the microtubule. Subsequently, the system disassembles to release the aggresome. The aggresome then recruits chaperone to be degraded by the autophagy machinery (Garcia Mata R et al. 1999).
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