E3 SUMO-protein ligase PIAS3 is an enzyme that in humans is encoded by the PIAS3 gene.[5][6]
PIAS family
The mammalian PIAS family consists of four members: PIAS1, PIAS2, PIAS3 and PIAS4. In Drosophila, a single PIAS homologue named dPIAS/Zimp has been identified.[7] In yeast, two PIAS-related proteins were identified namely SIZ1 and SIZ2.[8] The PIAS family contains more than 60 proteins, most of them transcription factors that can be either positively or negatively regulated through multiple mechanisms.
Discovery
IAS proteins were originally identified in studies that were aimed to decipher the Janus Kinase (JAK)/STAT signaling pathway. Originally, PIAS3 was found to interact specifically with phosphorylated STAT3 in Interleukin -6 (IL-6) activated murine myeloblast M1 cells.[9] This interaction is mediated via PIAS3 binding to the STAT3 DNA binding domain. Hence, STAT3 transcriptional activity is inhibited by the physical prevention of its binding to target genes. Subsequently, PIAS3 was also found to be a regulator protein of other key transcription factors, including MITF,[10]NFκB,[11]SMAD[12] and estrogen receptor.[13]
Function
PIAS3 protein also functions as a SUMO (small ubiquitin-like modifier)-E3 ligase which catalyzes the covalent attachment of a SUMO protein to specific target substrates. It directly binds to several transcription factors and either blocks or enhances their activity. Alternatively spliced transcript variants of this gene have been identified, but the full-length nature of some of these variants has not been determined.[6]
Domains
The SAF-A/B, Acinus and PIAS (SAP) domain is located at the N-terminal of PIAS proteins.[14] This evolutionarily conserved domain is found in proteins ranging from yeast to human and is shared by other chromatin-binding proteins, such as scaffold attachment factor A and B.[15] The SAP domain can recognize and bind to AT-rich DNA sequences present in scaffold-attachment regions/matrix-attachment regions.[16] These elements are frequently found near gene enhancers and interact with nuclear matrix proteins to provide a unique nuclear microenvironment for transcriptional regulation. An LXXLL signature motif is present within the SAP domain of all PIAS proteins. This signature motif has been shown to mediate interactions between nuclear receptors and their co-regulators.[17] It is also essential for the binding of PIAS3 to androgen receptor. The LXXLL motif represents the minimal requirement for the interaction with the NFκB p65 subunit and for the inhibition of NFκB transcriptional activity.[11] It was previously described that the LXXLL motif is also responsible for the retention of PIAS3 in the nucleus.
The Pro-Ile-Asn-Ile-Thr (PINIT) motif represents a highly conserved region of PIAS proteins, which was shown to be involved in the nuclear retention of PIAS3.[18] Within the PINIT domain, the PIAS382-132 region was isolated and characterized as an inhibitory domain that binds and inhibits both the MITF and STAT3 transcription factors.[19] The RING-finger-like zinc-binding domain (RLD) is one of the most conserved domains of the PIAS family and has been shown to be important for PIAS3 activity as a SUMO-E3 ligase.[20] The RLD domain is also involved in the positive regulation of SMAD3 by PIAS3.[21]
^Mohr SE, Boswell RE (Mar 1999). "Zimp encodes a homologue of mouse Miz1 and PIAS3 and is an essential gene in Drosophila melanogaster". Gene. 229 (1–2): 109–16. doi:10.1016/s0378-1119(99)00033-5. PMID10095110.
^Islam HK, Fujioka Y, Tomidokoro T, Sugiura H, Takahashi T, Kondo S, Katoh H (2001). "Immunohistochemical study of genetic alterations in intraductal and invasive ductal tumors of the pancreas". Hepato-Gastroenterology. 48 (39): 879–83. PMID11462947.
^Levy C, Khaled M, Fisher DE (Sep 2006). "MITF: master regulator of melanocyte development and melanoma oncogene". Trends in Molecular Medicine. 12 (9): 406–14. doi:10.1016/j.molmed.2006.07.008. PMID16899407.
^Yagil Z, Nechushtan H, Kay G, Yang CM, Kemeny DM, Razin E (May 2010). "The enigma of the role of protein inhibitor of activated STAT3 (PIAS3) in the immune response". Trends Immunol. 31 (5): 199–204. doi:10.1016/j.it.2010.01.005. PMID20181527.
Yamamoto T, Sato N, Sekine Y, Yumioka T, Imoto S, Junicho A, Fuse H, Matsuda T (Jun 2003). "Molecular interactions between STAT3 and protein inhibitor of activated STAT3, and androgen receptor". Biochemical and Biophysical Research Communications. 306 (2): 610–5. doi:10.1016/S0006-291X(03)01026-X. hdl:2115/28119. PMID12804609.
Di Y, Li J, Zhang Y, He X, Lu H, Xu D, Ling J, Huo K, Wan D, Li YY, Gu J (Jun 2003). "HCC-associated protein HCAP1, a variant of GEMIN4, interacts with zinc-finger proteins". Journal of Biochemistry. 133 (6): 713–8. doi:10.1093/jb/mvg091. PMID12869526.
Cheng J, Zhang D, Zhou C, Marasco WA (Jan 2004). "Down-regulation of SHP1 and up-regulation of negative regulators of JAK/STAT signaling in HTLV-1 transformed cell lines and freshly transformed human peripheral blood CD4+ T-cells". Leukemia Research. 28 (1): 71–82. doi:10.1016/S0145-2126(03)00158-9. PMID14630083.
Nojiri S, Joh T, Miura Y, Sakata N, Nomura T, Nakao H, Sobue S, Ohara H, Asai K, Ito M (Jan 2004). "ATBF1 enhances the suppression of STAT3 signaling by interaction with PIAS3". Biochemical and Biophysical Research Communications. 314 (1): 97–103. doi:10.1016/j.bbrc.2003.12.054. PMID14715251.
Wang L, Banerjee S (Jun 2004). "Differential PIAS3 expression in human malignancy". Oncology Reports. 11 (6): 1319–24. doi:10.3892/or.11.6.1319. PMID15138572.
