Ataxin-3 is a ubiquitously expressed nuclear protein that serves as a deubiquitinating enzyme (DUB) involved in protein homeostasis and quality control, myogenesis and degradation of misfolded chaperone substrates. As a DUB, it has two distinct features. Its N-terminal Josephin domain confers cysteine protease activity to Ataxin-3 which is important for hydrolyzing ubiquitin (Ub) linkages. The second important feature is its three Ub-interacting motifs (UIMs) through which it binds Ub conjugates and ubiquitinated proteins and bring them into proximity to trim or edit specific linkages within these Ub conjugates. It binds long poly-Ub chains and trims them. However, it has weak or no activity against chains of 4 or less Ub.
Cyclic AMP-dependent transcription factor ATF-1(ATF1) which contains 1 bZIP (basic-leucine zipper) domain and 1 KID (kinase-inducible) domain, belongs to the bZIP family. It influences cellular physiologic processes by regulating the expression of downstream target genes, which are related to growth, survival, and other cellular activities. ATF1 binds the cAMP response element (CRE) (consensus: 5'-GTGACGT[AC][AG]-3'), a sequence present in many viral and cellular promoters. It also binds to the Tax-responsive element (TRE) of HTLV-I. ATF1 mediates PKA-induced stimulation of CRE-reporter genes, represses the expression of FTH1 and other antioxidant detoxification genes, triggers cell proliferation and transformation. ATF1 is phosphorylated at serine 63 in its kinase-inducible domain by serine/threonine kinases, cAMP-dependent protein kinase A, calmodulin-dependent protein kinase I/II, mitogen- and stress-activated protein kinase and CDK3. Its phosphorylation enhances its transactivation and transcriptional activities, and enhances cell transformation.
Activating transcription factor 2, also known as ATF2, is a member of the leucine zipper family of DNA-binding proteins that binds to the cAMP response element. Its activity is enhanced after phosphorylation by stress-activated protein kinases such as c-Jun N-terminal kinase and p38. ATF2 has been found to be a target of the JNK signal transduction pathway and mediate adenovirus E1A-inducible transcriptional activation. ATF2 is also been reported playing roles in TGF-β signaling pathway. It has been shown that the transcription factor ATF2 is bound by a hetero-oligomer of Smad3 and Smad4 upon TGF-β stimulation. Studies indicate that ATF-2 plays a central role in TGF-β signaling by acting as a common nuclear target of both Smad and TAK1 pathways.
Ubiquitin-Like-Conjugating Enzyme ATG10 (ATG10) is a ubiquitous 28kDa member of the ATG10 family protein. ATG10 acts as an E2-like enzyme, catalyzes the transfer of ATG12 to ATG5 during in the initial stages of autophagesome formation. The heterodimer of ATG5 and ATG12 subsequntly associates non-covalently with an ATG16 multimer to generate an antophagosome. ATG10 plays a role in the conjugation of ATG12 to ATG5 by interaction with MAP1LC3A. In addition, ATG10 can diretly interact with ATG5 or ATG7.
Ubiquitin-like-conjugating enzyme ATG3 (ATG3), also known as Apg3L and Apg3p, functions as a regulatory component of autophagosome biogenesis necessary for autophagy. ATG3 exhibits 98% aa sequence identity with both its mouse and rat orthologs. It is widely expressed and has highly levels in heart, skeletal muscle, kidney, liver and placenta. As an E2-like enzyme, involves in autophagy and mitochondrial homeostasis. ATG3 catalyzes the conjugation of ATG8-like proteins to PE which is essential for autophagy. ATG3 also can catalyze the conjugation of ATG12 to itself which palys a role in mitochondrial homeostasis but not in autophagy.
Cysteine Protease ATG4A (ATG4A) is a cytoplasmic protein that belongs to the peptidase C54 family. ATG4A is widely expressed in many tissues at a low level, but the highest expression is observed in skeletal muscle and brain. ATG4A is a cysteine protease required for autophagy; it cleaves the C-terminal part of MAP1LC3, GABARAPL2 or GABARAP. ATG4A is inhibited by N-ethylmaleimide. It is suggested that ATG4A has a significant role in suppressing various cancers.
ATG5 is an E2 ubiquitin ligase which is necessary for autophagy. Its expression is a relatively late event in the apoptotic process, occurring downstream of caspase activity, dramatically highly expressed in apoptotic cells. It is activated by ATG7, conjugates to ATG12 and associates with isolation membrane to form cup-shaped isolation membrane and autophagosome. The conjugate complex detaches from the membrane immediately before or after autophagosome formation is completed. ATG5 plays an important role in the apoptotic process, possibly within the modified cytoskeleton.
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